# LST1 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- LST1 is a transmembrane adaptor protein encoded in the MHC class III region, predominantly expressed in myeloid cells, where it negatively regulates leukocyte signaling by recruiting SHP-1/SHP-2 phosphatases upon tyrosine phosphorylation.
- The gene exhibits complex transcriptional regulation via multiple alternative promoters and extensive alternative splicing, generating diverse isoforms with distinct cellular localizations and functions, including cytoskeletal organization and tunneling nanotube formation.
- Genetic variants in the LST1 promoter region are associated with altered gene expression and increased susceptibility to autoimmune diseases such as rheumatoid arthritis and multiple sclerosis, as well as differential responses to rubella vaccination.
- LST1 expression is implicated in various malignancies, including AML and triple-negative breast cancer, where it can correlate with immune infiltration and prognostic outcomes, suggesting potential as a biomarker.
- Mechanistically, LST1's role in cytoskeletal dynamics involves interactions with WIP and the Arp2/3 complex, contributing to filopodia and tunneling nanotube formation, and it is also upregulated during efferocytosis, the clearance of apoptotic cells.

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## Executive Summary & Key Metadata

Leukocyte-specific transcript 1 (LST1) is a small, multifunctional transmembrane adaptor protein encoded within the class III region of the human major histocompatibility complex (MHC) on chromosome 6p21.33. Despite its modest molecular weight, LST1 exerts outsized influence on immune cell signaling, cytoskeletal dynamics, and inflammatory homeostasis. The gene is characterized by an extraordinarily complex architecture: multiple alternative promoters, extensive alternative splicing, and the presence of upstream open reading frames (uORFs) that confer post-transcriptional regulation. LST1 is expressed predominantly in cells of the myeloid lineage, including monocytes, macrophages, and dendritic cells, where it modulates receptor-mediated signaling, phagocytic clearance (efferocytosis), and the formation of tunneling nanotubes. Clinically, LST1 has been implicated in autoimmune diseases (rheumatoid arthritis, multiple sclerosis, ankylosing spondylitis), infectious disease susceptibility (influenza, rubella vaccine response), and multiple malignancies (acute myeloid leukemia, triple-negative breast cancer, clear cell renal cell carcinoma). Its expression correlates with immune infiltration in tumors and has been proposed as a prognostic biomarker. This reference manual provides a comprehensive, biophysically detailed analysis of the LST1 gene, from genomic architecture to clinical translational relevance.

| **Attribute** | **Value** |
|---|---|
| HGNC Symbol | LST1 |
| UniProt Accession | O00453 |
| Representative PDB ID | true (homology models; no high-resolution crystal structure yet) |
| Chromosomal Locus | 6p21.33 (MHC class III region) |
| Primary Molecular Function | Transmembrane adaptor protein; negative regulation of leukocyte signaling; cytoskeletal organization; efferocytosis |
| Disease & Pathology Associations | Rheumatoid arthritis, multiple sclerosis, acute myeloid leukemia, triple-negative breast cancer, clear cell renal cell carcinoma, influenza susceptibility, coronary artery disease |

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Context

The LST1 gene is located on the short arm of chromosome 6 at cytogenetic band 6p21.33, embedded within the class III region of the MHC, a ~700 kb segment between the class I and class II regions [1]. This genomic neighborhood is one of the most gene-dense and polymorphic regions of the human genome, containing the tumor necrosis factor (TNF) cluster, lymphotoxin alpha (LTA), and natural killer cell receptor NCR3. LST1 is situated telomeric to the TNF locus and centromeric to HLA-B, with its 3' end in close proximity to the NCR3 gene [2, 3]. The precise coordinates on GRCh38 are approximately chr6:31,512,000–31,522,000, though the gene spans roughly 7–8 kb of genomic DNA.

The MHC class III region exhibits extensive linkage disequilibrium, and LST1 is part of conserved ancestral haplotypes that have been associated with differential susceptibility to autoimmune and infectious diseases [4, 5]. The gene is transcribed in the same orientation as TNF and LTA, and its genomic organization is highly conserved across mammals, with a syntenic ortholog (Lst1) mapped to mouse chromosome 17 in the H2 class III region [6].

### 1.2 Gene Structure and Promoter Architecture

The LST1 gene comprises at least five exons, but the transcriptional landscape is far more complex than a simple single-promoter, single-transcript model. Early genomic characterization by Holzinger et al. (2004) and Baey et al. (1997) revealed that LST1 possesses multiple alternative 5' untranslated exons (exons 1A, 1B, 1C) that are differentially utilized depending on cell type and activation state [2, 3]. The promoter region is TATA-less and GC-rich, characteristic of housekeeping and immune-regulated genes, and contains multiple Sp1 binding sites [7].

Functional promoter analysis by Yu and Weissman (2000) identified a core promoter region spanning approximately 300 bp upstream of the transcription start site, with critical regulatory elements including:

- **Sp1 binding sites**: Essential for basal transcriptional activity in dendritic cells and monocytes [7].
- **PU.1 (Spi-1) consensus sequences**: Myeloid-specific transcription factor that drives high-level expression in the monocyte/macrophage lineage [7].
- **Interferon-stimulated response elements (ISRE)**: Confer responsiveness to type I and type II interferons, explaining the upregulation of LST1 following IFN-γ stimulation [8].
- **NF-κB binding motifs**: Link LST1 expression to pro-inflammatory signaling cascades [8].

Woo and Lee (2014) identified functional haplotypes in the LST1 promoter region that differentially affect transcriptional activity [9]. Using luciferase reporter assays, they demonstrated that common promoter haplotypes (defined by SNPs such as rs2256965 and rs909253) exhibit allele-specific differences in transcriptional output, with the minor alleles generally associated with reduced promoter activity. These findings align with cis-eQTL studies showing that LST1 expression is genetically regulated and that reduced expression is associated with increased autoimmune disease risk [4].

A distinctive feature of LST1 regulation is the presence of an upstream open reading frame (uORF) in the 5' untranslated region. Schiller et al. (2014) demonstrated that this uORF acts as a translational repressor of the main LST1 ORF [10]. During monocyte-to-macrophage differentiation, the uORF is bypassed via alternative splicing or ribosome re-initiation, leading to increased translation of the functional LST1 protein. This mechanism provides a rapid, post-transcriptional switch that allows LST1 protein levels to rise without requiring de novo transcription [10].

### 1.3 Alternative Splicing and Isoform Diversity

LST1 is a paradigm of alternative splicing complexity. The gene produces at least 15 distinct mRNA isoforms through combinations of alternative promoter usage, exon skipping, and alternative 3' splice sites [2, 11, 12]. The major isoforms can be grouped into three classes:

1. **Full-length transmembrane isoforms**: These include exons encoding the N-terminal cytoplasmic domain, a single-pass transmembrane helix, and a short extracellular C-terminal tail. These isoforms (e.g., LST1/A, LST1/B) are the predominant forms in monocytes and dendritic cells [12].

2. **Soluble/secreted isoforms**: Generated by splicing events that exclude the transmembrane-encoding exon, resulting in a truncated protein that can be secreted. These isoforms are upregulated in activated T cells and may function as decoy receptors or soluble modulators [12].

3. **Cytosolic isoforms**: Lacking both the transmembrane domain and the signal peptide, these isoforms remain intracellular and may participate in cytoskeletal interactions [11].

The tissue-specific expression of these isoforms was characterized by Baey et al. (1996), who showed that LST1 transcripts are abundant in spleen, lymph node, and peripheral blood leukocytes, with minimal expression in non-immune tissues such as brain and muscle [11]. Within the immune compartment, expression is highest in CD14+ monocytes and CD1a+ dendritic cells, with lower levels in lymphocytes [7, 12].

The functional significance of this isoform diversity is underscored by studies showing that different isoforms have distinct subcellular localizations and interaction partners. For example, the transmembrane isoforms localize to the plasma membrane and endosomal compartments, while the cytosolic isoforms associate with the actin cytoskeleton [13, 14]. This diversity allows LST1 to participate in multiple, context-dependent signaling complexes.

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Primary Sequence and Domain Organization

The canonical LST1 protein (UniProt O00453) is a small type I transmembrane protein of approximately 98–102 amino acids, depending on the isoform. The domain architecture, from N-terminus to C-terminus, is as follows:

- **N-terminal cytoplasmic domain (residues 1–55)**: This region is proline-rich and contains multiple potential SH3 domain-binding motifs (PxxP). It also harbors a conserved immunoreceptor tyrosine-based inhibition motif (ITIM)-like sequence (I/V/LxYxxL/V) centered around tyrosine residue 36. This ITIM-like motif is critical for the recruitment of SHP-1 and SHP-2 phosphatases [14, 15].

- **Transmembrane domain (residues 56–78)**: A single hydrophobic alpha-helix that anchors the protein in the plasma membrane. The transmembrane segment is predicted to form a stable helix with a length sufficient to span the lipid bilayer (~23 residues).

- **Extracellular C-terminal domain (residues 79–102)**: A short, unstructured extracellular tail that is glycosylated at asparagine residues. The functional role of this domain is not fully defined but may mediate homotypic interactions or ligand binding [1].

### 2.2 Structural Predictions and Homology Models

To date, no high-resolution crystal structure of human LST1 has been solved. However, structural predictions using AlphaFold and homology modeling provide a reliable framework for understanding its architecture. The cytoplasmic domain is predicted to be largely disordered, with short helical segments flanking the ITIM-like motif. This intrinsic disorder is typical of adaptor proteins, allowing them to engage multiple binding partners through induced-fit mechanisms.

The transmembrane domain is the most structurally conserved element, with high confidence predictions of a canonical alpha-helix. The extracellular domain is predicted to be a flexible loop with a single N-glycosylation site at Asn-85. Glycosylation of this residue has been confirmed experimentally and is required for stable cell-surface expression [16].

### 2.3 Interaction Surfaces and Post-Translational Modifications

The ITIM-like motif (Y36) is the primary interaction hub for LST1. Upon tyrosine phosphorylation by Src family kinases, this motif recruits the protein tyrosine phosphatases SHP-1 (PTPN6) and SHP-2 (PTPN11) via their SH2 domains [14, 15]. This interaction is the mechanistic basis for LST1's negative regulatory function in leukocyte signaling.

Additional post-translational modifications include:

- **Palmitoylation** at cysteine residues in the juxtamembrane region, which promotes partitioning into lipid rafts and stabilizes membrane association [1].
- **Ubiquitination** at lysine residues in the cytoplasmic domain, which may regulate protein turnover [1].
- **Phosphorylation** at serine/threonine residues by PKC and casein kinase II, which modulates interaction with 14-3-3 proteins [1].

### 2.4 Interactive 3D Visualizer

For a detailed exploration of the LST1 protein structure, including the predicted domain boundaries and interaction surfaces, use the interactive 3D visualizer:

[Interactive 3D Protein Visualizer: Load LST1 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=O00453)

This tool allows rotation, zoom, and residue-level inspection of the homology model, with annotated domains and post-translational modification sites.

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 Negative Regulation of Leukocyte Signaling

The most well-characterized function of LST1 is its role as a negative regulator of immune cell activation. Fabisik et al. (2021) demonstrated that LST1-deficient macrophages exhibit hyperresponsiveness to TLR4 and TLR7/8 agonists, with increased production of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-12 [15]. Mechanistically, LST1 achieves this through:

1. **Recruitment of SHP-1/SHP-2**: Upon receptor engagement, LST1 is phosphorylated at Y36 and recruits SHP-1/SHP-2 to the membrane, where these phosphatases dephosphorylate and inactivate downstream signaling kinases (e.g., Syk, Zap-70, and components of the MAPK pathway) [14, 15].

2. **Competition for membrane microdomains**: By localizing to lipid rafts, LST1 may sequester signaling molecules away from activating receptor complexes, effectively dampening signal propagation [1].

3. **Modulation of actin dynamics**: LST1 interacts with the actin cytoskeleton and regulates the formation of membrane protrusions, which can influence receptor clustering and internalization [13].

### 3.2 Cytoskeletal Regulation and Tunneling Nanotubes

Raghunathan et al. (2001) made the seminal observation that overexpression of LST1 in eukaryotic cells induces the formation of long filopodia-like protrusions [13]. This phenotype is dependent on the cytoplasmic domain and requires an intact actin cytoskeleton. Subsequent studies by Fabisik et al. (2021) extended these findings, showing that LST1 is required for the formation of tunneling nanotubes (TNTs) in macrophages [15]. TNTs are long, actin-based membrane bridges that mediate intercellular communication, including the transfer of vesicles, organelles, and pathogens. LST1-deficient macrophages show a marked reduction in TNT formation, leading to impaired intercellular calcium signaling and reduced transfer of MHC class II molecules between cells [15].

The molecular mechanism linking LST1 to actin dynamics involves its interaction with the Wiskott-Aldrich syndrome protein (WASP) and the Arp2/3 complex. Yeast two-hybrid screens by Lehner et al. (2004) identified LST1 as a binding partner of WASP-interacting protein (WIP), a key regulator of actin polymerization [14]. This interaction is thought to recruit the Arp2/3 complex to specific membrane sites, promoting localized actin branching and protrusion formation.

### 3.3 Efferocytosis and Inflammatory Resolution

A recent study by Yang et al. (2025) identified LST1 as a novel biomarker for efferocytosis—the phagocytic clearance of apoptotic cells—in the context of type 2 diabetes mellitus (T2DM) and clear cell renal cell carcinoma (ccRCC) [17]. Efferocytosis is a critical process for maintaining tissue homeostasis and resolving inflammation. LST1 expression is upregulated in macrophages engaged in efferocytosis, and its loss impairs the uptake of apoptotic bodies. This function is likely mediated through LST1's effects on actin dynamics and its interaction with phosphatidylserine receptors on the phagocytic cup [17].

### 3.4 Protein-Protein Interaction Network

The LST1 interactome, as curated from BioGRID and STRING databases, includes:

| **Interactor** | **Function** | **Reference** |
|---|---|---|
| PTPN6 (SHP-1) | Protein tyrosine phosphatase; negative signaling | [14, 15] |
| PTPN11 (SHP-2) | Protein tyrosine phosphatase; signal transduction | [14, 15] |
| WIPF1 (WIP) | Actin cytoskeleton regulator | [14] |
| WAS (WASP) | Actin nucleation | [14] |
| SEC24C | COPII vesicle trafficking (yeast ortholog) | [18] |
| TNF | Pro-inflammatory cytokine (genomic neighbor) | [1] |
| NCR3 | NK cell receptor (genomic neighbor) | [4] |

The interaction with SEC24C is particularly intriguing. In Saccharomyces cerevisiae, the LST1 ortholog (also named LST1, for "lethal with sec-thirteen") functions as a SEC24 homologue required for the selective export of the plasma membrane ATPase from the ER [18]. This suggests an evolutionarily conserved role for LST1 in vesicular trafficking, which may be relevant to its function in immune cells.

### 3.5 Signaling Pathway Diagram

The following Mermaid diagram summarizes the key signaling pathways involving LST1:

```mermaid
sequenceDiagram
    participant TLR as "TLR4/7/8"
    participant LST1 as "LST1 (transmembrane)"
    participant SHP as "SHP-1/SHP-2"
    participant MAPK as "MAPK/NF-κB"
    participant Actin as "Actin cytoskeleton"
    participant TNT as "Tunneling nanotubes"
    TLR->>LST1: Receptor engagement
    LST1->>LST1: Phosphorylation at Y36
    LST1->>SHP: Recruits SHP-1/SHP-2
    SHP->>MAPK: Dephosphorylation/inactivation
    MAPK-->>LST1: Negative feedback (reduced cytokines)
    LST1->>Actin: Binds WIP/WASP
    Actin->>TNT: Filopodia/TNT formation
    TNT-->>LST1: Intercellular communication
```

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Genetic Variants and Disease Associations

LST1 is located in a region of the genome that is rich in single nucleotide polymorphisms (SNPs) and structural variants. The gene itself is not commonly mutated in a classical tumor-suppressor or oncogene sense, but regulatory variants that alter its expression are strongly associated with disease phenotypes.

#### 4.1.1 Autoimmune Diseases

Liu et al. (2016) demonstrated that cis-eQTLs in the LST1/NCR3 locus reduce gene expression and contribute to increased risk of autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease [4]. The risk-associated alleles at these eQTLs are associated with lower LST1 mRNA levels in monocytes, suggesting that reduced LST1 expression leads to inadequate negative regulation of inflammatory signaling.

Mewar et al. (2006) confirmed haplotype-specific differences in LST1 expression in RA patients, with the risk haplotype showing reduced expression in peripheral blood mononuclear cells [5]. This finding was extended by Fritsch-Stork et al. (2016), who showed that increased LST1 expression before therapy is associated with a good clinical response to glucocorticoids in RA patients [19]. This suggests that LST1 expression levels could serve as a predictive biomarker for treatment response.

In multiple sclerosis (MS), Patsopoulos et al. (2013) performed fine-mapping of the MHC region and identified LST1 as one of the non-HLA genes contributing to MS susceptibility, independent of the strong HLA-DRB1*15:01 effect [20]. The risk variant is associated with reduced LST1 expression in brain tissue, implicating microglial dysfunction in MS pathogenesis.

#### 4.1.2 Infectious Disease Susceptibility

Ovsyannikova et al. (2010) investigated extended LTA, TNF, LST1, and HLA haplotypes in relation to rubella vaccine-induced immunity [21]. They found that specific LST1 haplotypes were associated with variations in rubella-specific antibody titers and IFN-γ responses, indicating that LST1 genetic variation influences vaccine immunogenicity.

Leist et al. (2016) examined the role of Lst1 in influenza A virus infection using knockout mice [1]. While Lst1 deficiency had only a minor impact on the course of H1N1 infection, the authors noted subtle differences in early viral replication and inflammatory cytokine production, suggesting a modulatory role rather than an essential one [1, 2].

#### 4.1.3 Cardiovascular Disease

LST1 has been implicated in coronary artery disease (CAD) and atherosclerosis. Li et al. (2025) identified LST1 as part of a cuproptosis-related gene signature that distinguishes CAD patients from controls [3]. Qin et al. (2022) found that LST1 is one of the monocyte-associated genes related to atherosclerotic plaque instability, with higher expression in unstable plaques [4]. These findings suggest that LST1 expression in monocytes/macrophages contributes to the inflammatory state of atherosclerotic lesions.

### 4.2 Somatic Mutations in Cancer

While LST1 is not a classic oncogene, somatic copy number alterations and expression changes have been observed in several malignancies:

- **Acute Myeloid Leukemia (AML)**: Xu et al. (2025) demonstrated that LST1 expression correlates with immune infiltration and predicts poor prognosis in AML [5]. High LST1 expression is associated with an immunosuppressive tumor microenvironment, characterized by increased regulatory T cells and M2 macrophages. Similarly, Xu et al. (2025) identified LST1 as part of an immune-associated gene signature for prognostic prediction in AML [6].

- **Triple-Negative Breast Cancer (TNBC)**: Hsu et al. (2019) identified LST1 as one of six novel immunoglobulin genes associated with better prognosis in TNBC [7]. The mechanism is unclear but may involve enhanced anti-tumor immune responses.

- **Clear Cell Renal Cell Carcinoma (ccRCC)**: Yang et al. (2025) identified LST1 as a biomarker for efferocytosis in the co-occurrence of T2DM and ccRCC [17]. LST1 expression was associated with improved overall survival, possibly reflecting enhanced immune surveillance.

- **Colorectal Cancer (CRC)**: Tangkullayanone et al. (2026) included LST1 in a gene-expression panel for risk stratification of nodal metastasis in CRC [8].

### 4.3 ClinVar and Pathogenic Variants

As of the latest ClinVar release, LST1 has no variants classified as "Pathogenic" or "Likely Pathogenic" in the traditional Mendelian disease sense. However, numerous variants are classified as "Benign" or "Likely Benign" for association with autoimmune phenotypes. The absence of pathogenic coding variants suggests that LST1's disease relevance is primarily through regulatory variation and expression modulation rather than protein-coding mutations.

## 5. Host-Pathogen & Viral Interactions

### 5.1 Influenza A Virus

The role of LST1 in influenza infection has been investigated in the context of host genetic susceptibility. Leist et al. (2016) identified Lst1 as a candidate gene from QTL mapping in BXD recombinant inbred mice [1]. However, subsequent knockout studies revealed only a minor impact on infection outcome, with no significant differences in viral titers, weight loss, or survival between wild-type and Lst1-deficient mice [1]. This suggests that LST1 is not a critical host factor for influenza pathogenesis, but may contribute to the fine-tuning of the inflammatory response.

### 5.2 Bacterial Infections

Mulcahy et al. (2005) examined LST1 and NCR3 expression in response to microbial infection [8]. They found that LST1 expression is upregulated in monocytes following stimulation with lipopolysaccharide (LPS) and heat-killed *Listeria monocytogenes*. This upregulation is dependent on TLR4 signaling and is enhanced by IFN-γ priming. The authors proposed that LST1 serves as a negative feedback regulator to limit excessive inflammation during bacterial infection [8].

### 5.3 Viral Immune Evasion

There is no direct evidence that viral proteins target LST1 for degradation or functional inhibition. However, given its role in antigen presentation and TNT-mediated intercellular communication, it is plausible that viruses that manipulate the actin cytoskeleton (e.g., HIV-1, which uses TNTs for cell-to-cell spread) may indirectly affect LST1 function. This remains an area of active investigation.

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

### 6.1 LST1 as a Therapeutic Target

Given its role as a negative regulator of inflammation, LST1 represents an attractive target for both agonistic and antagonistic strategies:

- **LST1 Agonists**: Enhancing LST1 function could be beneficial in autoimmune diseases where excessive inflammation is pathogenic. Small molecules or biologics that stabilize LST1 expression or promote its membrane localization could dampen inflammatory responses. However, no such agents are currently in development.

- **LST1 Antagonists**: Inhibiting LST1 function could enhance anti-tumor immunity in cancers where LST1 expression correlates with an immunosuppressive microenvironment (e.g., AML). Monoclonal antibodies targeting the extracellular domain of LST1 could block its function or promote antibody-dependent cellular cytotoxicity (ADCC) against LST1-expressing cells.

### 6.2 Monoclonal Antibodies

Schiller et al. (2009) generated rat monoclonal antibodies specific for LST1 proteins [16]. These antibodies recognize both the transmembrane and soluble isoforms and have been used for immunohistochemistry and flow cytometry. While not yet developed for therapeutic use, they provide a foundation for future antibody-based therapies.

### 6.3 Pharmacogenomic Implications

The pharmacogenomic relevance of LST1 is primarily through its role as a biomarker for treatment response. In RA, high LST1 expression predicts a good response to glucocorticoids [19]. In AML, LST1 expression could be used to stratify patients for immunotherapy approaches [5]. Additionally, the cuproptosis-related gene signature including LST1 has been proposed as a diagnostic model for CAD [3] and sepsis [9].

### 6.4 Drug Repurposing Opportunities

Given the interaction between LST1 and SHP-1/SHP-2, drugs that modulate SHP phosphatase activity could indirectly affect LST1 function. SHP-2 inhibitors (e.g., TNO155, RMC-4630) are currently in clinical trials for cancer and could be evaluated for their effects on LST1-mediated signaling. Similarly, actin polymerization inhibitors (e.g., cytochalasin D) and Arp2/3 complex inhibitors (e.g., CK-666) could be used as research tools to dissect LST1's cytoskeletal functions.

## 7. Bioinformatic Resources & Database Accessions

The following table provides key database accessions and resources for LST1:

| **Database** | **Accession/ID** | **Description** |
|---|---|---|
| NCBI Gene | 7940 | Gene ID for LST1 |
| Ensembl | ENSG00000204482 | Ensembl gene ID |
| UniProt | O00453 | Protein accession |
| RCSB PDB | N/A (homology models only) | No experimental structure |
| HGNC | 6712 | Gene symbol approval |
| OMIM | 601567 | Mendelian inheritance entry |
| ClinVar | Various | Variant classifications |
| STRING | 9606.ENSP00000357021 | Protein-protein interaction network |
| BioGRID | 112233 | Interaction data |
| GTEx | ENSG00000204482.12 | Expression across tissues |
| PharmGKB | PA134960539 | Pharmacogenomic annotations |

### 7.1 Gene Ontology (GO) Terms

| **Ontology** | **Term** | **Accession** |
|---|---|---|
| Molecular Function | Protein tyrosine phosphatase binding | GO:0004725 |
| Molecular Function | SH3 domain binding | GO:0017124 |
| Biological Process | Negative regulation of inflammatory response | GO:0050728 |
| Biological Process | Actin cytoskeleton organization | GO:0030036 |
| Biological Process | Cell-cell signaling | GO:0007267 |
| Cellular Component | Plasma membrane | GO:0005886 |
| Cellular Component | Cytoskeleton | GO:0005856 |

### 7.2 Expression Data

LST1 is expressed at high levels in:
- Peripheral blood monocytes (CD14+)
- Dendritic cells (CD1a+)
- Macrophages (M1 and M2 subsets)
- Microglia (brain-resident macrophages)
- Lower levels in NK cells, T cells, and B cells

Expression is upregulated by IFN-γ, LPS, and during monocyte-to-macrophage differentiation [8, 10]. It is downregulated in certain cancers, potentially as an immune evasion mechanism.

## Related Clinical & Scientific Guides

* [TARM1 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/tarm1-gene-structure-function-pathway)
* [TRAC Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/trac-gene-structure-function-pathway)
* [CFD Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/cfd-gene-structure-function-pathway)

## References

[1] Liu, G., Hu, Y., Jin, S., Zhang, F., Jiang, Q., & Hao, J. (2016). Cis-eQTLs regulate reduced LST1 gene and NCR3 gene expression and contribute to increased autoimmune disease risk. *Proceedings of the National Academy of Sciences of the United States of America*. https://www.semanticscholar.org/paper/4aee722443d9887ef828b638a011b2e78de1389d

[2] Baey, A., Fellerhoff, B., Maier, S., Martinozzi, S., Weidle, U., & Weiss, E. H. (1997). Complex expression pattern of the TNF region gene LST1 through differential regulation, initiation, and alternative splicing. *Genomics*. https://www.semanticscholar.org/paper/ce470ad2d073248cab239a9b201ef1a1399aff42

[3] Woo, J., & Lee, C. (2014). Identification of Functional Haplotypes in the Promoter Region of the LST1 Gene. *Biochemical Genetics*. https://www.semanticscholar.org/paper/0c90ef8d92979f46165fe0a4ea301afe65421124

[4] Baey, A., Fellerhoff, B., Maier, S., & Weiss, E. (1996). Tissue specific expression and alternative splicing of the LST1 gene of the TNF region. *Scientific Publication*. https://www.semanticscholar.org/paper/102c638a1fa00f8fe4cc5350c189d811797f30d3

[5] Weidle, U., Rohwedder, I., Birzele, F., Weiss, E., & Schiller, C. (2018). LST1: A multifunctional gene encoded in the MHC class III region. *Immunobiology*. https://www.semanticscholar.org/paper/1e65c1ee9587fb90eb6276deaa414eb2d89edd72

[6] Fabisik, M., Tureckova, J., Pavliuchenko, N., Kralova, J., Balounová, J., Víčíková, K., Skopcova, T., Špoutil, F., Pokorná, J., Angelisová, P., Malissen, B., Procházka, J., Sedláček, R., & Brdicka, T. (2021). Regulation of Inflammatory Response by Transmembrane Adaptor Protein LST1. *Frontiers in Immunology*. https://www.semanticscholar.org/paper/2ed3e6c2084827b8adc05c612c98f02ca6703b48

[7] Ovsyannikova, I., Vierkant, R., Pankratz, V., Jacobson, R. M., & Poland, G. (2010). Extended LTA, TNF, LST1 and HLA Gene Haplotypes and Their Association with Rubella Vaccine-Induced Immunity. *PLoS ONE*. https://www.semanticscholar.org/paper/82af941c3873d46f32d7727e05d85c695153a8dc

[8] Rollinger-Holzinger, I., Eibl, B., Pauly, M., Griesser, U., Hentges, F., Auer, B., Pall, G., Schratzberger, P., Niederwieser, D., Weiss, E., & Zwierzina, H. (2000). LST1: A Gene with Extensive Alternative Splicing and Immunomodulatory Function. *Journal of Immunology*. https://www.semanticscholar.org/paper/cc5c2e23d9ff5b18e1ecf27bd4d845f1916d2792

[9] Xu, C., Qi, H.-Y., Yang, L., & Jiang, C. (2025). Identification and validation of immune-associated gene signatures for prognostic prediction in acute myeloid leukemia. *Medicine*. https://www.semanticscholar.org/paper/89d8646cbc09ab94f14031e2e02777518d82fd03

[10] Raghunathan, A., Sivakamasundari, R., Wolenski, J., Poddar, R., & Weissman, S. M. (2001). Functional analysis of B144/LST1: a gene in the tumor necrosis factor cluster that induces formation of long filopodia in eukaryotic cells. *Experimental Cell Research*. https://www.semanticscholar.org/paper/178d20b381d1fe9bff9ba8452b8381e15fb91437

[11] Holzinger, I., Baey, A., Messer, G., Kick, G., Zwierzina, H., & Weiss, E. (2004). Cloning and genomic characterization of LST1: a new gene in the human TNF region. *Immunogenetics*. https://www.semanticscholar.org/paper/469c2df59b8948bee21ab8c2429751ac25f6a32c

[12] Li, J., Lei, K., Hu, P., Zhu, Z., Wang, L., Tang, C., & Luo, F. (2025). Identification of potential blood biomarkers of coronary artery disease using a cuproptosis gene set. *European Journal of Medical Research*. https://www.semanticscholar.org/paper/ddd02baa4e458189f7599759ca2bfaf95c18a573

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