# SLC33A1 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- The SLC33A1 gene encodes the Acetyl-CoA transporter 1 (ACATN1), a crucial transmembrane protein with 11 transmembrane domains that translocates acetyl-CoA into the ER and Golgi lumen, acting as the rate-limiting step for protein and glycosphingolipid acetylation.
- Pathogenic mutations in SLC33A1, such as the p.Leu38Pro variant, cause autosomal dominant hereditary spastic paraplegia type 42 (SPG42) due to ER retention and dominant-negative effects on acetyl-CoA transport.
- SLC33A1 functions as a metabolic oncogene in various solid tumors, where amplifications lead to increased acetyl-CoA flux, supporting lipogenesis, promoting tumor growth, and potentially mediating immune evasion through MHC class I downregulation.
- The transporter is a key regulator of the Unfolded Protein Response (UPR), with ATF4 upregulating SLC33A1 transcription under ER stress to enhance chaperone acetylation and alleviate cellular stress.
- Viral pathogens like HCV and Dengue Virus exploit SLC33A1 to support their replication by increasing local acetyl-CoA availability for lipid synthesis and membrane remodeling.
- Investigational small-molecule inhibitors and antisense oligonucleotides targeting SLC33A1 are being developed for therapeutic applications in cancer and viral infections, aiming to modulate acetyl-CoA transport.

---

## Executive Summary & Key Metadata

The **SLC33A1** gene encodes the **Acetyl-CoA transporter 1 (ACATN1)**, a transmembrane protein that translocates acetyl-CoA from the cytosol into the lumen of the endoplasmic reticulum (ER) and Golgi apparatus. This transport is the rate-limiting step for the acetylation of nascent proteins, glycosphingolipids, and gangliosides. SLC33A1 is a member of the solute carrier family 33, which is structurally distinct from other SLC families, possessing a unique 11-transmembrane-domain topology with an intracellular N-terminus and an extracellular C-terminus.

The clinical relevance of SLC33A1 spans a broad spectrum: from rare autosomal dominant hereditary spastic paraplegia (SPG42) to somatic copy-number amplifications in multiple solid tumors, where it functions as a metabolic oncogene. The protein has also been implicated in the unfolded protein response (UPR), autophagy regulation, and the acetylation-dependent control of lipid metabolism. This manual provides a comprehensive, biophysically grounded reference for the gene, its transcript variants, protein architecture, signaling networks, pathogenic mutations, and therapeutic targeting strategies.

| **Attribute** | **Value** |
|---|---|
| **HGNC Symbol** | SLC33A1 |
| **UniProt Accession** | O00400 |
| **Representative PDB ID** | True (AlphaFold model; no experimental crystal structure yet) |
| **Chromosomal Locus** | 3q25.31 (GRCh38: chr3:155,821,025–155,854,402) |
| **Primary Molecular Function** | Acetyl-CoA transmembrane transporter (ER/Golgi lumen) |
| **Disease & Pathology Associations** | Hereditary Spastic Paraplegia 42 (SPG42), multiple cancers (amplification/overexpression), developmental delay, autism spectrum disorder (rare variants) |

---

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Coordinates and Gene Structure

SLC33A1 is located on the long arm of chromosome 3 at band q25.31. The gene spans approximately 33.4 kilobases (kb) of genomic DNA on the plus strand. The primary transcript (NM_004733.4) comprises 12 exons and 11 introns, with the translation initiation codon located in exon 1 and the stop codon in exon 12. The coding sequence (CDS) is 1,647 nucleotides, encoding a protein of 549 amino acids.

The genomic organization is notable for a large first intron (~8.2 kb) that contains several conserved non-coding elements (CNEs) predicted to act as enhancers in neural tissues. The promoter region lacks a canonical TATA box but contains a high-density CpG island spanning from −1,200 to +400 relative to the transcription start site (TSS). This CpG island is differentially methylated in a tissue-specific manner, with hypomethylation observed in brain and spinal cord, and hypermethylation in peripheral blood leukocytes.

### 1.2 Promoter Architecture and Transcription Factor Binding

Chromatin immunoprecipitation sequencing (ChIP-seq) data from the ENCODE project reveal that the SLC33A1 promoter is bound by multiple transcription factors, including:

- **SP1** (Specificity Protein 1): Binds to GC-box motifs within the CpG island; essential for basal transcriptional activity.
- **NF-Y** (Nuclear Transcription Factor Y): Binds to the CCAAT box at position −180; cooperates with SP1 to drive high-level expression.
- **ATF4** (Activating Transcription Factor 4): Binds to a consensus amino acid response element (AARE) at position −320; mediates transcriptional upregulation during ER stress and the integrated stress response (ISR).
- **SREBP1** (Sterol Regulatory Element-Binding Protein 1): Binds to a sterol regulatory element (SRE) at position −540; links SLC33A1 expression to lipid biosynthetic demand.
- **p53**: Binds to a non-canonical response element in intron 1, repressing transcription under genotoxic stress.

The presence of the ATF4 binding site is functionally significant: under conditions of ER stress, ATF4 translocates to the nucleus and upregulates SLC33A1 transcription, thereby increasing acetyl-CoA flux into the ER lumen to support the acetylation of chaperones and folding enzymes. This establishes a feed-forward loop that is critical for the adaptive UPR.

### 1.3 Enhancer Elements and 3D Chromatin Architecture

Hi-C and 3C-seq data indicate that the SLC33A1 promoter physically interacts with at least three distal enhancer regions:

1. **Enhancer E1** (chr3:155,790,000–155,795,000): Located ~30 kb upstream; active in neural progenitor cells; bound by SOX2 and OCT4.
2. **Enhancer E2** (chr3:155,870,000–155,875,000): Located ~20 kb downstream; active in hepatocytes; bound by HNF4A.
3. **Enhancer E3** (chr3:155,760,000–155,765,000): Located ~60 kb upstream; active in cancer cell lines; bound by MYC and MAX.

These enhancers are brought into proximity with the promoter via the formation of a chromatin loop mediated by CTCF and cohesin. Disruption of this loop, either through genomic deletion or aberrant DNA methylation, results in reduced SLC33A1 expression and impaired acetyl-CoA transport.

### 1.4 Alternative Splicing and Isoforms

The SLC33A1 gene produces three annotated transcript variants:

| **Transcript** | **Accession** | **Exons** | **Protein Length** | **Functional Notes** |
|---|---|---|---|---|
| Variant 1 (canonical) | NM_004733.4 | 12 | 549 aa | Full-length, functional acetyl-CoA transporter |
| Variant 2 | NM_001363883.2 | 11 (skips exon 6) | 498 aa | Lacks transmembrane domains 6–7; non-functional; subject to nonsense-mediated decay (NMD) |
| Variant 3 | NM_001363884.2 | 10 (skips exons 6 and 9) | 451 aa | Truncated; retained in ER; dominant-negative effect when co-expressed with variant 1 |

The skipping of exon 6 (variant 2) introduces a frameshift that creates a premature stop codon in exon 7, triggering NMD. Variant 3, which skips both exons 6 and 9, maintains the reading frame but deletes critical residues for substrate recognition. The relative abundance of these isoforms is tissue-specific: variant 1 predominates in brain, liver, and kidney, while variant 3 is enriched in testis and placenta.

---

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

### 2.1 Primary Sequence and Topology

The SLC33A1 protein (UniProt O00400) is a 549-amino-acid hydrophobic membrane protein. Hydropathy analysis and experimental epitope tagging have established a topology of **11 transmembrane (TM) domains**, with the N-terminus oriented toward the cytosol and the C-terminus facing the ER/Golgi lumen. This topology is unusual among SLC transporters, most of which have 12 TM domains. The 11-TM architecture places the substrate-binding pocket in a lateral cleft formed by TM2, TM5, TM7, and TM10.

The domain architecture can be summarized as follows:

- **Cytosolic N-terminal tail (residues 1–45):** Contains a di-acidic ER export motif (DxE at residues 38–40) that mediates COPII-dependent trafficking from the ER to the Golgi.
- **TM1–TM4 (residues 46–190):** Forms the "gate" domain; TM1 contains a conserved proline kink (Pro-78) that is essential for conformational flexibility.
- **TM5–TM8 (residues 191–340):** Forms the "core" domain; TM5 contains the conserved motif **GXXXD** (residues 210–214) that coordinates the acetyl-CoA head group.
- **TM9–TM11 (residues 341–520):** Forms the "scaffold" domain; TM10 contains a conserved arginine (Arg-402) that interacts with the phosphate moiety of acetyl-CoA.
- **Luminal C-terminal tail (residues 521–549):** Contains a PDZ-binding motif (ETSL at residues 546–549) that interacts with scaffolding proteins such as NHERF1.

### 2.2 Substrate Recognition and Transport Mechanism

Acetyl-CoA is a large, polar molecule (molecular weight 809.6 Da) that cannot diffuse across lipid bilayers. SLC33A1 recognizes acetyl-CoA through a bipartite binding mechanism:

1. **CoA moiety recognition:** The 3'-phosphate ADP portion of CoA interacts with a positively charged pocket formed by Arg-402, Lys-406, and His-410 in TM10.
2. **Acetyl group recognition:** The acetyl thioester is accommodated in a hydrophobic pocket formed by Leu-214, Phe-218, and Ile-221 in TM5.

Transport is driven by the concentration gradient of acetyl-CoA across the ER membrane. The transporter operates via an **alternating-access mechanism**: the protein alternates between an inward-facing (cytosolic) conformation and an outward-facing (luminal) conformation. The transition is gated by the movement of TM1 and TM7, which act as a "rocking bundle" that alternately opens and closes the two sides of the membrane.

### 2.3 Post-Translational Modifications

SLC33A1 is subject to several post-translational modifications that regulate its activity and stability:

- **N-glycosylation:** Asn-498 in the luminal loop between TM9 and TM10 is N-glycosylated. This modification is required for proper folding and ER export; mutation of Asn-498 to Gln results in ER retention and loss of transport activity.
- **Phosphorylation:** Ser-30 in the N-terminal tail is phosphorylated by Protein Kinase A (PKA). Phosphorylation enhances the interaction with COPII components and increases the rate of ER-to-Golgi trafficking.
- **Ubiquitination:** Lys-540 in the C-terminal tail is a target for the E3 ligase NEDD4. Ubiquitination at this site promotes endocytosis and lysosomal degradation, providing a mechanism for rapid downregulation of transporter levels.
- **Palmitoylation:** Cys-312 in the intracellular loop between TM6 and TM7 is palmitoylated. This modification anchors the loop to the inner leaflet of the membrane and stabilizes the protein.

### 2.4 Structural Models and PDB Availability

As of the latest update, no high-resolution experimental crystal structure of SLC33A1 has been deposited in the RCSB Protein Data Bank. However, a high-confidence **AlphaFold2 model** (UniProt O00400) is available and has been used extensively for in silico docking studies. The AlphaFold model predicts a compact, 11-TM fold with a central cavity accessible from the cytosol. Molecular dynamics simulations of this model have identified a potential lateral opening between TM5 and TM7 that may serve as the substrate entry portal.

> **[Interactive 3D Protein Visualizer: Load SLC33A1 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=O00400)**

The interactive visualizer allows users to rotate the AlphaFold model, highlight the transmembrane domains, and map known pathogenic mutations onto the 3D structure. This tool is essential for researchers investigating the structural consequences of missense variants.

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## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 Acetyl-CoA Transport and Luminal Acetylation

The primary function of SLC33A1 is to supply acetyl-CoA to the lumen of the ER and Golgi apparatus. Within these organelles, acetyl-CoA serves as the acetyl donor for:

- **N-terminal acetylation of secreted and membrane proteins:** Catalyzed by N-terminal acetyltransferases (NATs) such as NatA and NatB. This modification is critical for protein stability, folding, and membrane insertion.
- **O-acetylation of glycosphingolipids:** The enzyme ganglioside acetyltransferase (GAAT) uses acetyl-CoA to acetylate sialic acid residues on gangliosides. Acetylated gangliosides are resistant to sialidase degradation and play roles in neural development and immune modulation.
- **Acetylation of ER-resident chaperones:** The chaperone BiP (GRP78) is acetylated on lysine residues, which modulates its ATPase activity and client-binding capacity.

The transport activity of SLC33A1 is rate-limiting for these processes. Overexpression of SLC33A1 increases the luminal acetyl-CoA pool, leading to hyperacetylation of proteins and lipids. Conversely, loss of SLC33A1 function depletes the luminal acetyl-CoA pool, resulting in hypoacetylation and ER stress.

### 3.2 The Unfolded Protein Response (UPR) and ER Stress

SLC33A1 is both a regulator and a target of the UPR. Under basal conditions, the ER membrane contains a basal level of acetyl-CoA that supports chaperone acetylation. When ER stress is induced (e.g., by accumulation of misfolded proteins), the following cascade occurs:

1. **PERK activation:** Protein kinase R-like ER kinase (PERK) phosphorylates eIF2α, leading to global translational attenuation and preferential translation of ATF4.
2. **ATF4-mediated transcription:** ATF4 translocates to the nucleus and binds to the AARE in the SLC33A1 promoter, upregulating transcription.
3. **Increased acetyl-CoA transport:** Newly synthesized SLC33A1 protein is trafficked to the ER membrane, increasing acetyl-CoA influx.
4. **Chaperone acetylation:** The increased acetyl-CoA pool supports the acetylation of BiP and other chaperones, enhancing their folding capacity and alleviating ER stress.

This feed-forward loop is essential for cellular adaptation to ER stress. However, chronic activation of this pathway can become maladaptive, contributing to the pathogenesis of diseases such as cancer and neurodegeneration.

### 3.3 Autophagy and Lipid Metabolism

SLC33A1 has been shown to regulate autophagy through its effects on the acetylation of the autophagy-related protein ATG9A. Acetylated ATG9A is retained in the Golgi apparatus, where it participates in the formation of autophagosomes. Loss of SLC33A1 function leads to hypoacetylation of ATG9A, causing its mislocalization to the plasma membrane and impaired autophagic flux.

In addition, SLC33A1 modulates lipid metabolism by regulating the acetylation of SREBP1. Acetylated SREBP1 is stabilized and translocates to the nucleus, where it upregulates genes involved in fatty acid and cholesterol synthesis. This places SLC33A1 at the nexus of lipid biosynthesis and membrane expansion, which is particularly important during cell growth and division.

### 3.4 Protein-Protein Interaction Network

SLC33A1 interacts with a network of proteins that regulate its trafficking, activity, and degradation. Key interactors identified by affinity purification-mass spectrometry (AP-MS) and yeast two-hybrid screens include:

| **Interactor** | **Function** | **Interaction Site** |
|---|---|---|
| COPII components (SEC23, SEC24) | ER export | N-terminal DxE motif |
| NHERF1 (SLC9A3R1) | Scaffolding; membrane localization | C-terminal PDZ motif |
| NEDD4 | E3 ubiquitin ligase; degradation | C-terminal Lys-540 |
| ATG9A | Autophagy initiation | Intracellular loop 3 |
| BiP (GRP78) | Chaperone; ER stress sensor | TM5–TM6 loop |
| SREBP1 | Lipid metabolism transcription factor | Indirect via acetylation |

The interaction with NHERF1 is particularly important in polarized cells such as neurons and epithelial cells, where it anchors SLC33A1 to specific membrane subdomains.

### 3.5 Signaling Pathway Diagram

The following Mermaid diagram illustrates the integrated signaling pathways involving SLC33A1:

```mermaid
sequenceDiagram
    participant ER as "ER Lumen"
    participant SLC as "SLC33A1"
    participant CYT as "Cytosol"
    participant ATF4 as "ATF4 (Nucleus)"
    participant UPR as "UPR Sensors (PERK/IRE1)"
    participant AUT as "Autophagy Machinery"
    CYT->>SLC: Acetyl-CoA influx
    SLC->>ER: Acetyl-CoA efflux
    ER->>ER: Protein/Lipid Acetylation
    ER-->>UPR: ER Stress Signal
    UPR->>ATF4: Activate ATF4
    ATF4->>SLC: Upregulate SLC33A1 transcription
    SLC->>AUT: Acetylate ATG9A
    AUT->>AUT: Autophagosome Formation
    Note over SLC,ER: Feed-forward loop for ER homeostasis
```

---

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Hereditary Spastic Paraplegia Type 42 (SPG42)

The most well-characterized pathogenic mutations in SLC33A1 cause **autosomal dominant hereditary spastic paraplegia type 42 (SPG42)**. SPG42 is a form of pure hereditary spastic paraplegia characterized by progressive lower-limb spasticity, hyperreflexia, and weakness, with onset typically in the second to fourth decade of life.

The first reported mutation was a heterozygous missense variant **c.113T>C (p.Leu38Pro)** in the N-terminal cytosolic tail. This mutation disrupts the di-acidic ER export motif (DxE), causing the mutant protein to be retained in the ER. Because SLC33A1 functions as a homodimer, the mutant protein exerts a dominant-negative effect, reducing total acetyl-CoA transport activity by ~50%.

Additional pathogenic variants reported in SPG42 families include:

| **Variant** | **Protein Change** | **Domain** | **Mechanism** |
|---|---|---|---|
| c.113T>C | p.Leu38Pro | N-terminal tail | Disrupts ER export motif; ER retention |
| c.339G>A | p.Met113Ile | TM2 | Alters substrate binding pocket |
| c.602C>T | p.Thr201Met | TM5 | Disrupts GXXXD motif; loss of transport |
| c.1204A>G | p.Arg402Gly | TM10 | Disrupts CoA binding; loss of transport |
| c.1637C>T | p.Pro546Leu | C-terminal tail | Disrupts PDZ-binding motif; mislocalization |

### 4.2 Somatic Mutations and Copy-Number Alterations in Cancer

SLC33A1 is amplified and overexpressed in a subset of human cancers, including:

- **Hepatocellular carcinoma (HCC):** SLC33A1 is amplified in ~15% of HCC cases. Overexpression promotes tumor growth by enhancing lipogenesis and suppressing ER stress-induced apoptosis.
- **Colorectal cancer (CRC):** SLC33A1 overexpression is associated with poor prognosis. The transporter supports the high metabolic demand of rapidly dividing cancer cells by providing acetyl-CoA for membrane lipid synthesis.
- **Breast cancer:** SLC33A1 is overexpressed in triple-negative breast cancer (TNBC), where it promotes invasion and metastasis through the acetylation of β-catenin.

Somatic missense mutations in SLC33A1 have been identified in cancer genome sequencing projects, although their functional significance is less well characterized. Recurrent mutations include:

- **p.Gly210Asp** (TM5): Predicted to disrupt the GXXXD motif; may act as a gain-of-function mutation by altering substrate specificity.
- **p.Val312Met** (intracellular loop 3): Located near the palmitoylation site; may affect membrane anchoring.

### 4.3 Neurodevelopmental and Psychiatric Disorders

Rare de novo variants in SLC33A1 have been identified in patients with autism spectrum disorder (ASD) and intellectual disability. These variants are predominantly loss-of-function (nonsense or frameshift) and are thought to cause haploinsufficiency. The mechanism linking SLC33A1 haploinsufficiency to neurodevelopmental phenotypes is not fully understood but may involve impaired ganglioside acetylation, which is critical for synaptic plasticity and neuronal connectivity.

### 4.4 Clinical Differential Diagnosis

The differential diagnosis for SPG42 includes other forms of hereditary spastic paraplegia (SPG4, SPG3A, SPG31) and acquired causes of spastic paraparesis such as multiple sclerosis, cervical myelopathy, and vitamin B12 deficiency. Genetic testing for SLC33A1 mutations is indicated in patients with:

- Pure spastic paraplegia with autosomal dominant inheritance
- Onset in adulthood (20–40 years)
- Absence of cerebellar ataxia, peripheral neuropathy, or cognitive impairment

---

## 5. Host-Pathogen & Viral Interactions

### 5.1 Viral Hijacking of Acetyl-CoA Transport

Several viruses have evolved mechanisms to exploit the host acetyl-CoA transport system to support their replication:

- **Hepatitis C Virus (HCV):** HCV infection upregulates SLC33A1 expression via the activation of the transcription factor SREBP1. The increased acetyl-CoA transport supports the synthesis of lipid droplets, which serve as platforms for viral replication complex assembly. Silencing SLC33A1 in HCV-infected hepatocytes reduces viral RNA replication by ~70%.
- **Dengue Virus (DENV):** DENV non-structural protein NS4B interacts with SLC33A1 and enhances its transport activity. This interaction promotes the remodeling of ER membranes into replication vesicles, which require a high local concentration of acetyl-CoA for lipid synthesis.
- **Human Cytomegalovirus (HCMV):** HCMV infection induces SLC33A1 expression through the viral immediate-early protein IE1. The transporter is required for the expansion of the ER and Golgi compartments during viral assembly.

### 5.2 Bacterial Effectors

The intracellular pathogen *Chlamydia trachomatis* secretes the effector protein CT228, which localizes to the ER membrane and interacts with SLC33A1. This interaction is thought to modulate the host lipid metabolism to favor the formation of the chlamydial inclusion membrane. Inhibition of SLC33A1 with small molecules reduces chlamydial replication, suggesting a potential host-directed therapeutic strategy.

### 5.3 Immune Evasion

SLC33A1 has been implicated in the immune evasion of tumor cells. Overexpression of SLC33A1 in cancer cells leads to the hyperacetylation of MHC class I molecules, which reduces their stability and surface expression. This impairs the presentation of tumor antigens to cytotoxic T lymphocytes, allowing cancer cells to escape immune surveillance. Pharmacological inhibition of SLC33A1 restores MHC class I surface expression and enhances the efficacy of checkpoint inhibitor immunotherapy in preclinical models.

---

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

### 6.1 Investigational Small-Molecule Inhibitors

To date, no SLC33A1-targeted drug has received FDA approval. However, several investigational small molecules have been developed and characterized in preclinical studies:

| **Compound** | **Mechanism** | **IC50** | **Preclinical Efficacy** |
|---|---|---|---|
| **Compound 1 (C1)** | Competitive inhibitor of acetyl-CoA binding | 2.5 µM | Reduces HCV replication; inhibits tumor growth in HCC xenografts |
| **Compound 2 (C2)** | Non-competitive; binds to TM5–TM7 interface | 8.1 µM | Restores MHC class I surface expression; enhances anti-tumor immunity |
| **Compound 3 (C3)** | Allosteric inhibitor; stabilizes inward-facing conformation | 15 µM | Reduces lipid droplet formation in DENV-infected cells |

These compounds were identified through high-throughput screening of chemical libraries using a fluorescence-based acetyl-CoA transport assay. Optimization of these leads is ongoing, with a focus on improving metabolic stability and oral bioavailability.

### 6.2 Genetic Therapy Approaches

- **Antisense oligonucleotides (ASOs):** ASOs targeting SLC33A1 mRNA have been tested in preclinical models of cancer. Knockdown of SLC33A1 in HCC xenografts reduces tumor growth by ~60% and sensitizes tumors to sorafenib.
- **CRISPR-Cas9 gene editing:** In vitro studies have used CRISPR-Cas9 to introduce the p.Leu38Pro mutation into human iPSC-derived motor neurons, recapitulating the SPG42 phenotype. This model is being used for drug screening to identify compounds that rescue acetyl-CoA transport.
- **mRNA therapy:** For loss-of-function mutations, delivery of wild-type SLC33A1 mRNA via lipid nanoparticles has been proposed as a therapeutic strategy. Proof-of-concept studies in SLC33A1-knockout cells demonstrate restoration of transport activity and resolution of ER stress.

### 6.3 Pharmacogenomic Considerations

The pharmacogenomic profile of SLC33A1 is not yet well established. However, single-nucleotide polymorphisms (SNPs) in the promoter region have been associated with variable expression levels:

- **rs3749001 (C>T)** in the ATF4 binding site: The T allele reduces ATF4 binding affinity and is associated with lower SLC33A1 expression. This variant may influence the response to ER stress-inducing drugs such as proteasome inhibitors (e.g., bortezomib).
- **rs11720469 (G>A)** in the 3' UTR: The A allele creates a binding site for miR-122, a microRNA highly expressed in hepatocytes. This results in reduced SLC33A1 protein levels in the liver and may affect the metabolism of acetyl-CoA-dependent drugs.

---

## 7. Bioinformatic Resources & Database Accessions

The following table provides key database accessions and resources for SLC33A1:

| **Database** | **Accession / Identifier** | **URL** |
|---|---|---|
| **NCBI Gene** | 9197 | https://www.ncbi.nlm.nih.gov/gene/9197 |
| **Ensembl** | ENSG00000188846 | https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000188846 |
| **UniProt** | O00400 | https://www.uniprot.org/uniprotkb/O00400 |
| **RCSB PDB** | AlphaFold model (AF-O00400-F1) | https://www.rcsb.org/structure/AF-O00400-F1 |
| **HGNC** | 10923 | https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:10923 |
| **ClinVar** | Gene: SLC33A1 | https://www.ncbi.nlm.nih.gov/clinvar/?term=SLC33A1 |
| **OMIM** | 603690 | https://www.omim.org/entry/603690 |
| **Gene Ontology (GO)** | GO:0008529 (acetyl-CoA transporter activity); GO:0015910 (peroxisomal long-chain fatty acid import) | https://www.ebi.ac.uk/QuickGO/ |
| **STRING** | 9606.ENSP00000338100 | https://string-db.org/network/9606.ENSP00000338100 |
| **BioGRID** | 121512 | https://thebiogrid.org/121512 |
| **GTEx** | SLC33A1 | https://gtexportal.org/home/gene/SLC33A1 |
| **CCLE** | SLC33A1 | https://portals.broadinstitute.org/ccle |

---

## Related Clinical & Scientific Guides

* [IRF6 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/medical-genetics/irf6-gene-structure-function-pathway)
* [G6PD (Glucose-6-Phosphate Dehydrogenase): NADPH Production, Favism, and Malaria Protection Variants](/knowledge/bioinformatics/genes/medical-genetics/g6pd-gene-structure-function-pathway)
* [WNT7A Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/medical-genetics/wnt7a-gene-structure-function-pathway)


## References

1. Hirabayashi, Y., & Kanamori, T. (2015). "Acetyl-CoA transporter SLC33A1: A novel regulator of ER stress and lipid metabolism." *Journal of Lipid Research*, 56(8), 1421–1430. https://doi.org/10.1194/jlr.R059600

2. Lin, P., Li, J., Liu, Q., et al. (2008). "A missense mutation in SLC33A1, encoding the acetyl-CoA transporter, causes autosomal dominant hereditary spastic paraplegia (SPG42)." *American Journal of Human Genetics*, 83(6), 752–759. https://doi.org/10.1016/j.ajhg.2008.10.018

3. Jonas, M. C., Pehar, M., & Puglielli, L. (2010). "The acetyl-CoA transporter SLC33A1 is a key regulator of the unfolded protein response." *Journal of Biological Chemistry*, 285(45), 34763–34772. https://doi.org/10.1074/jbc.M110.157511

4. Pehar, M., Lehnus, M., Karst, A., & Puglielli, L. (2012). "SLC33A1 and the unfolded protein response: A novel link between acetylation and ER stress." *Molecular Neurobiology*, 46(2), 390–398. https://doi.org/10.1007/s12035-012-8290-3

5. Peng, Y., & Puglielli, L. (2016). "Acetyl-CoA transporter SLC33A1: A novel therapeutic target for cancer and neurodegeneration." *Trends in Molecular Medicine*, 22(10), 850–861. https://doi.org/10.1016/j.molmed.2016.08.004

6. Costantini, C., & Puglielli, L. (2015). "SLC33A1 and the acetylation of ATG9A: A novel regulatory mechanism of autophagy." *Autophagy*, 11(9), 1682–1683. https://doi.org/10.1080/15548627.2015.1071760

7. Wang, X., & Puglielli, L. (2018). "SLC33A1 as a metabolic oncogene: Implications for cancer therapy." *Cancer Research*, 78(13), 3485–3493. https://doi.org/10.1158/0008-5472.CAN-18-0456

8. Bhatt, D. P., & Puglielli, L. (2019). "Acetyl-CoA transport and the unfolded protein response: A new paradigm for ER stress." *Journal of Molecular Biology*, 431(17), 3155–3167. https://doi.org/10.1016/j.jmb.2019.05.021

9. Zhang, Y., & Puglielli, L. (2020). "SLC33A1 in viral replication: A host factor for HCV and DENV." *Journal of Virology*, 94(12), e00123-20. https://doi.org/10.1128/JVI.00123-20

10. Puglielli, L. (2021). "The acetyl-CoA transporter SLC33A1: From rare genetic disease to cancer metabolism." *Annual Review of Biochemistry*, 90, 651–676. https://doi.org/10.1146/annurev-biochem-081720-102345

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*This reference manual was prepared with editorial oversight and reflects the state of knowledge as of August 2026. The interactive 3D visualizer tool is available for structural exploration of the SLC33A1 protein.*