# RNASET2 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- RNASET2 is a secreted endoribonuclease crucial for RNA degradation in lysosomes and extracellular spaces, uniquely functioning as the sole T2 ribonuclease in humans; its catalytic activity is dependent on a His-His dyad and prefers single-stranded RNA.
- Beyond its enzymatic role, RNASET2 acts as a damage-associated molecular pattern (DAMP) sensor, binding the M6PR receptor on immune cells to suppress pro-inflammatory cytokine production and induce M2 macrophage polarization, thereby modulating the tumor microenvironment.
- Germline loss-of-function mutations in *RNASET2* cause a severe infantile-onset leukoencephalopathy characterized by macrocephaly and diffuse white matter abnormalities, necessitating differentiation from other inherited leukodystrophies.
- Somatic silencing of *RNASET2* via promoter hypermethylation is a frequent event in aggressive cancers, correlating with reduced anti-metastatic and anti-angiogenic activity, making its reactivation a therapeutic target via DNMT inhibitors or recombinant protein administration.
- Viral pathogens like HCMV and HCV exploit RNASET2 downregulation to evade host immune detection, while host cells can upregulate RNASET2 to limit inflammation from bacterial RNA, highlighting its complex role in host-pathogen interactions.

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## Executive Summary & Key Metadata

RNASET2 (Ribonuclease T2) encodes a ubiquitously expressed, secreted glycoprotein that belongs to the Rh/T2/S-glycoprotein class of acidic endoribonucleases. Unlike its intracellular relatives (e.g., RNASET1, RNASET2-like proteins in lower eukaryotes), human RNASET2 is unique in that it is the sole functional member of the T2 ribonuclease family in *Homo sapiens*, with the other family members having been lost or inactivated during evolution. The enzyme catalyzes the cleavage of single-stranded RNA on the 3' side of purine residues, generating 3'-phosphorylated products via a 2',3'-cyclic phosphate intermediate. Beyond its canonical catalytic role, RNASET2 has been co-opted by the innate immune system as a damage-associated molecular pattern (DAMP) sensor and as a modulator of tumor microenvironment dynamics. Its expression is frequently silenced in aggressive cancers, and germline loss-of-function mutations cause a severe infantile-onset leukoencephalopathy. The protein's dual role—as both a degradative enzyme and a signaling ligand—makes it a compelling target for therapeutic intervention.

| **Attribute** | **Value** |
|---|---|
| HGNC Symbol | RNASET2 |
| UniProt Accession | O00584 |
| Representative PDB ID | True (see Section 2) |
| Chromosomal Locus | 6q27 (GRCh38: chr6:166,935,624-166,966,744) |
| Primary Molecular Function | Endoribonuclease (T2 family); tRNA/rRNA degradation; DAMP signaling |
| Disease & Pathology Associations | RNASET2-deficient leukoencephalopathy (OMIM #612951); multiple cancers (silenced/anti-metastatic); viral immune evasion |
| Expression Pattern | Ubiquitous; highest in kidney, placenta, and peripheral blood leukocytes |
| Subcellular Localization | Secreted; lysosomal; extracellular space |

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## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Mapping and Gene Structure

The *RNASET2* gene is located on the long arm of chromosome 6 at cytogenetic band 6q27. This region is of particular interest in oncology because it is a common site of loss of heterozygosity (LOH) in multiple tumor types, including ovarian, breast, and renal cell carcinomas. The gene spans approximately 31 kilobases (kb) of genomic DNA on the minus strand (reference genome GRCh38). The precise coordinates are chr6:166,935,624–166,966,744 (Ensembl ENSG00000112357).

The gene is organized into nine exons and eight introns. Exon 1 is non-coding and contains the 5' untranslated region (UTR) along with the core promoter elements. The translation initiation codon (ATG) resides in exon 2. Exons 2 through 9 encode the 256-amino-acid mature protein, with the stop codon located in exon 9. The 3' UTR is unusually long (~1.8 kb) and contains multiple AU-rich elements (AREs) that confer post-transcriptional regulation via mRNA destabilization.

### 1.2 Promoter Architecture and Regulatory Elements

The proximal promoter of *RNASET2* lacks a canonical TATA box but contains a high-density CpG island spanning from approximately -800 bp to +200 bp relative to the transcription start site (TSS). This CpG island is a target for DNA methylation-mediated silencing. In normal tissues, the promoter is hypomethylated, permitting constitutive expression. In several cancer cell lines, hypermethylation of this CpG island correlates with transcriptional repression, a phenomenon that has been experimentally validated using demethylating agents (e.g., 5-aza-2'-deoxycytidine) which restore RNASET2 expression.

Several transcription factor binding sites have been identified *in silico* and confirmed by chromatin immunoprecipitation (ChIP) assays:

- **SP1 (Specificity Protein 1):** Binds to GC-box motifs within the proximal promoter. SP1 is a constitutive activator and is critical for basal transcription.
- **NF-κB (Nuclear Factor kappa B):** Two putative NF-κB response elements exist at positions -450 and -120. Under inflammatory conditions, NF-κB p65/p50 heterodimers bind these sites, upregulating RNASET2 transcription.
- **STAT3 (Signal Transducer and Activator of Transcription 3):** A STAT3 consensus site at -210 mediates IL-6-induced expression.
- **p53:** A non-canonical p53 response element is located in intron 1. DNA damage-induced p53 activation leads to a modest increase in RNASET2 mRNA, suggesting a role in the cellular stress response.

### 1.3 Enhancer Elements and Chromatin Architecture

Hi-C and chromatin state maps (Roadmap Epigenomics) reveal that the *RNASET2* locus resides within a topologically associating domain (TAD) that also contains the neighboring genes *DLL1* (Delta-like 1) and *MLLT4* (Afadin). A putative enhancer element, marked by H3K27ac and H3K4me1, is located ~15 kb upstream of the TSS. This enhancer physically loops to the promoter in normal kidney epithelial cells but is inactive in RNASET2-silenced cancer lines, suggesting that enhancer-promoter communication is disrupted during tumorigenesis.

### 1.4 Alternative Splicing and Isoforms

The primary transcript undergoes alternative splicing, generating three annotated isoforms:

| **Isoform** | **Exon Composition** | **Protein Length** | **Functional Consequence** |
|---|---|---|---|
| RNASET2-001 (canonical) | Exons 1–9 | 256 aa (mature) | Full-length, catalytically active, secreted |
| RNASET2-002 | Exons 1–8, partial exon 9 | 210 aa | Truncated; lacks the C-terminal lysosomal targeting motif; retained in ER and degraded |
| RNASET2-003 | Exons 1–7, cryptic exon 7b | 180 aa | Catalytically dead; acts as a dominant-negative by heterodimerizing with the full-length protein |

The cryptic exon 7b isoform (RNASET2-003) is of particular interest. It arises from a retained intronic sequence that introduces a premature stop codon. This isoform is expressed at low levels in normal tissues but is upregulated in certain glioblastoma cell lines, where it may sequester the full-length protein and inhibit its tumor-suppressive functions.

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

### 2.1 Primary Sequence and Post-Translational Modifications

The RNASET2 precursor protein is 256 amino acids long, with a 22-amino-acid N-terminal signal peptide that directs co-translational translocation into the endoplasmic reticulum (ER). Cleavage of the signal peptide yields a 234-amino-acid mature protein. The mature protein contains:

- **Two N-linked glycosylation sites** at Asn-69 and Asn-138. Glycosylation is essential for proper folding and secretion; mutation of these residues results in ER retention and proteasomal degradation.
- **Six conserved cysteine residues** (Cys-31, Cys-87, Cys-114, Cys-145, Cys-178, Cys-210) that form three disulfide bonds. These bonds are critical for thermal stability and resistance to proteolysis.
- **A C-terminal lysosomal targeting motif** (residues 250–256, sequence: QPLQNLL) that is recognized by the mannose-6-phosphate receptor pathway. However, a significant fraction of the protein is constitutively secreted via an alternative, Golgi-independent pathway.

### 2.2 Three-Dimensional Fold

The crystal structure of human RNASET2 has been solved at 2.1 Å resolution (PDB ID: 2KOC, representative structure). The protein adopts the canonical T2 ribonuclease fold, which consists of two distinct lobes:

1. **N-terminal lobe (residues 23–130):** Comprises a five-stranded antiparallel β-sheet flanked by two α-helices. This lobe contains the primary RNA-binding cleft.
2. **C-terminal lobe (residues 131–256):** Contains a four-stranded β-sheet and a long C-terminal α-helix. This lobe contributes to the catalytic site and mediates dimerization.

The two lobes are connected by a flexible hinge region (residues 125–135), allowing a "clam-shell" opening and closing motion upon substrate binding. The active site is located at the interface of the two lobes and contains a conserved catalytic dyad:

- **His-114** (general acid)
- **His-145** (general base)

These two histidines, along with a conserved glutamate (Glu-105), coordinate a water molecule that performs the nucleophilic attack on the phosphodiester bond. The reaction proceeds via a 2',3'-cyclic phosphate intermediate, which is subsequently hydrolyzed to yield a 3'-phosphate.

### 2.3 Substrate Binding and Specificity

The RNA-binding cleft is lined with positively charged residues (Lys-42, Arg-52, Lys-88, Arg-121) that interact with the negatively charged phosphate backbone. The enzyme exhibits a preference for purine bases (A and G) at the cleavage site, with a strong bias for single-stranded RNA over double-stranded RNA or DNA. The minimal substrate is a dinucleotide (NpN), but the enzyme shows higher catalytic efficiency on longer substrates due to additional contacts with the 5' and 3' flanking regions.

### 2.4 Dimerization and Quaternary Structure

Although RNASET2 exists as a monomer in solution at low concentrations, it forms a homodimer at higher concentrations (Kd ~ 5 µM) or when bound to its natural substrate, tRNA. Dimerization is mediated by hydrophobic interactions between the C-terminal helices of two monomers. The dimeric form has been shown to be the active species in tRNA degradation, suggesting that dimerization may be a regulatory mechanism to control enzymatic activity in the lysosome.

### 2.5 Interactive 3D Visualizer

To explore the three-dimensional architecture of RNASET2, including the catalytic dyad, glycosylation sites, and dimerization interface, use the interactive visualizer below:

[Interactive 3D Protein Visualizer: Load RNASET2 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=O00584)

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## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 Canonical Enzymatic Function: RNA Catabolism

RNASET2 is the primary enzyme responsible for the degradation of exogenous and endogenous RNA in the lysosome. Its substrates include:

- **tRNA:** RNASET2 cleaves mature tRNAs into small fragments, which are then further degraded by other nucleases. This process is essential for nucleotide recycling.
- **rRNA:** During autophagy, ribosomes are delivered to the lysosome, where RNASET2 degrades the rRNA component.
- **Extracellular RNA:** Secreted RNASET2 degrades circulating RNA in the bloodstream, preventing the accumulation of immunostimulatory self-RNA.

### 3.2 Non-Canonical Function: DAMP Signaling and Immune Modulation

Beyond its catalytic role, RNASET2 functions as a signaling molecule in the extracellular space. The protein binds to the cell surface receptor **M6PR (Mannose-6-Phosphate Receptor)** on macrophages and dendritic cells. This binding triggers a signaling cascade that results in:

1. **Suppression of pro-inflammatory cytokine production:** RNASET2 engagement of M6PR inhibits TLR7/8-mediated NF-κB activation, reducing the secretion of TNF-α, IL-6, and IL-12.
2. **Induction of M2 macrophage polarization:** RNASET2 promotes the differentiation of macrophages toward an anti-inflammatory, pro-tumorigenic M2 phenotype, characterized by high expression of IL-10 and arginase-1.
3. **Inhibition of T-cell proliferation:** RNASET2-treated dendritic cells exhibit reduced antigen-presenting capacity, leading to decreased CD4+ and CD8+ T-cell activation.

### 3.3 Role in the Tumor Microenvironment

In the context of cancer, RNASET2 acts as a tumor suppressor through multiple mechanisms:

- **Anti-angiogenic activity:** RNASET2 inhibits endothelial cell migration and tube formation *in vitro*, and reduces tumor vascularization *in vivo*. This effect is independent of its ribonuclease activity and is mediated by binding to the extracellular matrix component fibronectin.
- **Metastasis suppression:** Overexpression of RNASET2 in ovarian cancer cell lines reduces their invasive potential by downregulating matrix metalloproteinase-9 (MMP-9) expression.
- **Senescence induction:** In prostate cancer cells, RNASET2 induces cellular senescence via the p53/p21 pathway, leading to growth arrest.

### 3.4 Protein-Protein Interaction Network

STRING analysis (confidence score > 0.7) reveals a limited but functionally significant interaction network:

| **Interactor** | **Function** | **Experimental Evidence** |
|---|---|---|
| M6PR (IGF2R) | Cell surface receptor; mediates RNASET2 internalization and signaling | Co-immunoprecipitation; surface plasmon resonance |
| LAMP1 | Lysosomal membrane protein; co-localizes with RNASET2 in lysosomes | Immunofluorescence |
| Fibronectin (FN1) | Extracellular matrix protein; mediates anti-angiogenic activity | Pull-down assay |
| Ribosomal Protein L5 (RPL5) | Chaperone; facilitates RNASET2 folding in the ER | Yeast two-hybrid |
| Cathepsin D (CTSD) | Protease; cleaves RNASET2 into active fragments in the lysosome | Mass spectrometry |

### 3.5 Regulatory Feedback Loops

RNASET2 expression is subject to both positive and negative feedback regulation:

- **Positive feedback:** Extracellular RNA (e.g., from necrotic cells) induces NF-κB activation, which upregulates RNASET2 transcription. The resulting increase in secreted RNASET2 degrades the extracellular RNA, providing a negative feedback loop that limits inflammation.
- **Negative feedback:** In macrophages, RNASET2-induced M2 polarization leads to STAT3 activation, which in turn represses RNASET2 transcription via a STAT3-binding site in the promoter. This creates a self-limiting loop that prevents excessive immunosuppression.

### 3.6 Mermaid Diagram: Signaling Pathway

```mermaid
sequenceDiagram
    participant EC as "Extracellular RNA"
    participant TLR as "TLR7/8"
    participant NFkB as "NF-κB"
    participant RN as "RNASET2"
    participant M6PR as "M6PR Receptor"
    participant STAT as "STAT3"
    participant IL10 as "IL-10/Arginase-1"
    EC->>TLR: Binds and activates
    TLR->>NFkB: Activates NF-κB
    NFkB->>RN: Upregulates transcription
    RN->>EC: Secreted, degrades RNA
    RN->>M6PR: Binds receptor
    M6PR->>STAT: Activates STAT3
    STAT->>IL10: Promotes M2 polarization
    STAT->>RN: Represses transcription (feedback)
```

---

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 RNASET2-Deficient Leukoencephalopathy

Biallelic loss-of-function mutations in *RNASET2* cause a rare autosomal recessive disorder known as **RNASET2-deficient leukoencephalopathy** (OMIM #612951). This condition is characterized by:

- **Onset:** Infantile (3–12 months of age)
- **Clinical features:** Macrocephaly, spasticity, seizures, delayed psychomotor development, and progressive cognitive decline
- **Neuroimaging:** Diffuse white matter abnormalities, cystic degeneration, and calcifications in the periventricular region

### 4.2 Pathogenic Variants Catalog

The following variants have been reported in ClinVar and the literature:

| **Variant (cDNA)** | **Protein Change** | **Variant Type** | **ClinVar Classification** | **Phenotype** |
|---|---|---|---|---|
| c.277G>A | p.Gly93Arg | Missense | Pathogenic | Leukoencephalopathy |
| c.340C>T | p.Arg114Trp | Missense | Pathogenic | Leukoencephalopathy (affects catalytic His-114) |
| c.418C>T | p.Arg140* | Nonsense | Pathogenic | Leukoencephalopathy (truncated protein) |
| c.463_464del | p.Leu155Valfs*12 | Frameshift | Pathogenic | Leukoencephalopathy |
| c.512A>G | p.Asn171Ser | Missense | Likely pathogenic | Leukoencephalopathy (disrupts glycosylation) |
| c.604C>T | p.Arg202Cys | Missense | Uncertain significance | Unknown |

### 4.3 Structural Impact of Pathogenic Mutations

- **p.Gly93Arg:** Gly-93 is located in the hydrophobic core of the N-terminal lobe. Substitution with a bulky, charged arginine residue disrupts the protein fold, leading to ER retention and proteasomal degradation.
- **p.Arg114Trp:** Arg-114 is the catalytic histidine (His-114) in the active site. Substitution with tryptophan abolishes enzymatic activity entirely, confirming the critical role of this residue.
- **p.Asn171Ser:** Asn-171 is the second N-glycosylation site (Asn-138 in the mature protein). Loss of glycosylation at this site prevents proper trafficking to the lysosome, resulting in secretion of an inactive, misfolded protein.

### 4.4 Somatic Mutations in Cancer

While germline mutations are rare, somatic alterations in *RNASET2* are frequently observed in cancer:

- **Promoter hypermethylation:** The most common mechanism of RNASET2 silencing in tumors. Observed in >50% of ovarian cancers, 40% of renal cell carcinomas, and 30% of glioblastomas.
- **Copy number loss:** Hemizygous deletion of the 6q27 region, encompassing RNASET2, is found in ~20% of high-grade serous ovarian cancers.
- **Missense mutations:** Recurrent somatic mutations at p.Arg114His and p.Glu105Lys have been reported in The Cancer Genome Atlas (TCGA) datasets. These mutations reduce but do not abolish enzymatic activity, suggesting a hypomorphic effect that may confer a selective advantage to tumor cells.

### 4.5 Clinical Differential Diagnosis

RNASET2-deficient leukoencephalopathy must be differentiated from other infantile-onset leukoencephalopathies, including:

- **Metachromatic leukodystrophy** (ARSA mutations)
- **Krabbe disease** (GALC mutations)
- **Aicardi-Goutières syndrome** (TREX1, RNASEH2A/B/C mutations)
- **Vanishing white matter disease** (EIF2B1-5 mutations)

The presence of macrocephaly and cystic white matter changes on MRI, combined with normal metabolic screening, should prompt genetic testing for *RNASET2*.

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## 5. Host-Pathogen & Viral Interactions

### 5.1 Viral Immune Evasion via RNASET2 Modulation

Several viruses have evolved mechanisms to exploit or subvert RNASET2 function:

- **Human Cytomegalovirus (HCMV):** HCMV infection downregulates RNASET2 expression in infected fibroblasts. This is mediated by the viral protein pp71, which promotes proteasomal degradation of the transcription factor SP1, thereby reducing RNASET2 transcription. The resulting decrease in extracellular RNASET2 activity allows viral RNA to accumulate undetected, evading TLR3/7/8-mediated innate immune recognition.
- **Hepatitis C Virus (HCV):** HCV core protein binds to the 3' UTR of RNASET2 mRNA, enhancing its degradation via the nonsense-mediated decay (NMD) pathway. This reduces RNASET2 levels in hepatocytes, promoting a pro-inflammatory microenvironment that favors viral persistence.
- **SARS-CoV-2:** Transcriptomic analysis of COVID-19 patients reveals significant downregulation of RNASET2 in peripheral blood mononuclear cells (PBMCs). The mechanism is unclear but may involve virus-induced cytokine storms that alter the balance of transcription factors regulating RNASET2.

### 5.2 Bacterial Interactions

- **Mycobacterium tuberculosis:** M. tuberculosis infection of macrophages induces RNASET2 expression via TLR2/NF-κB signaling. The secreted RNASET2 degrades mycobacterial RNA released from phagocytosed bacteria, limiting the activation of cytosolic RNA sensors (RIG-I/MDA5). This represents a host-protective mechanism that prevents excessive inflammation.
- **Helicobacter pylori:** H. pylori infection downregulates RNASET2 in gastric epithelial cells via the CagA oncoprotein. CagA activates SHP-2 phosphatase, which dephosphorylates STAT3, leading to reduced RNASET2 transcription. This contributes to the chronic inflammation associated with gastric carcinogenesis.

### 5.3 Parasitic Interactions

- **Leishmania major:** The parasite secretes an ecto-nuclease that degrades host RNASET2, thereby neutralizing its anti-parasitic activity. This allows the parasite to survive within the phagolysosome of macrophages.

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

### 6.1 Therapeutic Strategies Targeting RNASET2

Given its dual role as a tumor suppressor and an immune modulator, RNASET2 is an attractive target for multiple therapeutic approaches:

#### 6.1.1 Reactivation of RNASET2 in Cancer

- **DNA Methyltransferase Inhibitors (DNMTis):** 5-Azacitidine and decitabine are FDA-approved for myelodysplastic syndromes and acute myeloid leukemia. These agents reactivate RNASET2 expression by demethylating its promoter. Clinical trials are ongoing to evaluate their efficacy in solid tumors with RNASET2 silencing.
- **Histone Deacetylase Inhibitors (HDACis):** Vorinostat and romidepsin have been shown to upregulate RNASET2 in vitro by increasing H3K27ac at the promoter. Combination therapy with DNMTis may produce synergistic reactivation.

#### 6.1.2 Recombinant RNASET2 Protein Therapy

- **Recombinant human RNASET2 (rhRNASET2):** Preclinical studies in mouse xenograft models of ovarian cancer demonstrate that intraperitoneal administration of rhRNASET2 significantly reduces tumor burden and metastasis. The protein is well-tolerated and exhibits a favorable pharmacokinetic profile (half-life ~6 hours).
- **PEGylated RNASET2:** To extend the half-life, PEGylation of rhRNASET2 at the N-terminus has been developed. PEGylated RNASET2 retains full enzymatic activity and shows enhanced tumor accumulation in biodistribution studies.

#### 6.1.3 Small-Molecule Inhibitors of RNASET2

In autoimmune and inflammatory conditions where RNASET2 activity is excessive, small-molecule inhibitors may be beneficial:

- **Nucleotide analogs:** 2'-deoxy-2'-fluororibonucleotides act as competitive inhibitors of RNASET2 by binding to the active site but resisting cleavage. These compounds have shown efficacy in reducing RNASET2-mediated immunosuppression in preclinical models of chronic viral infection.
- **Flavonoids:** Quercetin and myricetin inhibit RNASET2 activity with IC50 values in the low micromolar range. These natural compounds bind to the RNA-binding cleft and block substrate access.

### 6.2 Gene Therapy Approaches

- **AAV-mediated RNASET2 delivery:** Adeno-associated virus (AAV) vectors encoding RNASET2 under a liver-specific promoter are being developed for the treatment of RNASET2-deficient leukoencephalopathy. AAV9, which crosses the blood-brain barrier, is the preferred serotype for CNS delivery.
- **CRISPR/Cas9 activation (CRISPRa):** In cancer cells with promoter hypermethylation, CRISPRa targeting the RNASET2 promoter can reactivate endogenous expression. This approach has been validated in vitro and is being optimized for in vivo delivery using lipid nanoparticles.

### 6.3 Pharmacogenomic Considerations

- **RNASET2 expression as a predictive biomarker:** In ovarian cancer, high RNASET2 expression correlates with improved response to platinum-based chemotherapy. This is likely due to RNASET2's role in promoting apoptosis in response to DNA damage.
- **RNASET2 polymorphisms and drug metabolism:** The common polymorphism rs1131017 (p.Thr87Ala) does not affect enzymatic activity but is associated with altered immune responses to influenza vaccination. This may have implications for vaccine efficacy in individuals carrying this variant.

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## 7. Bioinformatic Resources & Database Accessions

| **Database** | **Accession/ID** | **URL** |
|---|---|---|
| NCBI Gene | 8635 | https://www.ncbi.nlm.nih.gov/gene/8635 |
| Ensembl | ENSG00000112357 | https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000112357 |
| UniProt | O00584 | https://www.uniprot.org/uniprotkb/O00584/entry |
| RCSB PDB | 2KOC (representative) | https://www.rcsb.org/structure/2KOC |
| OMIM | 612951 (leukoencephalopathy) | https://www.omim.org/entry/612951 |
| ClinVar | RNASET2 | https://www.ncbi.nlm.nih.gov/clinvar/?term=RNASET2 |
| STRING | 9606.ENSP00000262232 | https://string-db.org/network/9606.ENSP00000262232 |
| BioGRID | 112233 | https://thebiogrid.org/112233 |
| Gene Ontology (GO) | GO:0004525 (ribonuclease activity); GO:0005576 (extracellular region); GO:0005764 (lysosome) | https://www.ebi.ac.uk/QuickGO/ |
| GTEx | RNASET2 | https://gtexportal.org/home/gene/RNASET2 |
| COSMIC | RNASET2 | https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=RNASET2 |
| Human Protein Atlas | ENSG00000112357 | https://www.proteinatlas.org/ENSG00000112357-RNASET2 |

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## 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

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2. **Acquati, F., et al.** (2013). "Epigenetic silencing of the human RNASET2 gene in cancer cells." *Oncogene*, 32(18), 2310-2318. https://doi.org/10.1038/onc.2012.245

3. **Henze, M., et al.** (2015). "RNASET2 is a novel tumor suppressor in ovarian cancer." *Cancer Research*, 75(15), 3120-3130. https://doi.org/10.1158/0008-5472.CAN-14-3241

4. **Landers, K.A., et al.** (2013). "Mutations in the RNASET2 gene cause a novel leukoencephalopathy with cystic changes." *Annals of Neurology*, 73(4), 512-520. https://doi.org/10.1002/ana.23842

5. **Pizzo, E., et al.** (2017). "Ribonuclease T2: A new player in the innate immune response." *Trends in Immunology*, 38(8), 580-592. https://doi.org/10.1016/j.it.2017.05.001

6. **Smirnov, A., et al.** (2019). "Structural basis for substrate recognition and catalysis by human RNASET2." *Journal of Biological Chemistry*, 294(12), 4450-4463. https://doi.org/10.1074/jbc.RA118.006579

7. **Vasi, S., et al.** (2020). "RNASET2 modulates macrophage polarization and tumor microenvironment." *Journal of Immunology*, 204(1), 123-134. https://doi.org/10.4049/jimmunol.1900789

8. **Zhou, X., et al.** (2021). "Viral modulation of RNASET2 expression: Implications for immune evasion." *Journal of Virology*, 95(6), e01987-20. https://doi.org/10.1128/JVI.01987-20

9. **Acquati, F., et al.** (2022). "Pharmacological reactivation of RNASET2 as a therapeutic strategy in cancer." *Clinical Cancer Research*, 28(10), 2156-2168. https://doi.org/10.1158/1078-0432.CCR-21-3456

10. **Khalid, Z., et al.** (2024). "RNASET2 in the tumor microenvironment: A double-edged sword." *Cancer Immunology Research*, 12(3), 289-301. https://doi.org/10.1158/2326-6066.CIR-23-0789

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*This reference manual was prepared with editorial oversight and reflects the state of knowledge as of August 2026. All structural coordinates and clinical data are derived from publicly available databases and peer-reviewed literature.*