基因總覽
RNASEL 是蛋白質編碼基因，其產物 ribonuclease L 為內切核糖核酸酶，屬於 protein kinase 超家族。蛋白質長 741 個胺基酸，包含九個 ANK 重複序列、Protein kinase domain、KEN domain，以及兩段與 2-5A 結合相關的區域。其結構也包括 atypical C6-type zinc finger；蛋白質兩端各有一段被註記為無序的區域。這些特徵構成辨識與活化所需的蛋白質架構，使 ribonuclease L 能在抗病毒反應中擔任 RNA 代謝相關酵素。
基因異名與舊稱
異名取自 HGNC，可能包含歷史名稱；蛋白質名稱以 UniProt 註解為準。
染色體位置與基因結構
查看實際轉錄本與 exon 註解
| Transcript | Genomic coordinates | Exons |
|---|---|---|
| ENST00000367559 ★ | 182,573,634–182,589,256 | 7 |
| ENST00001114075 | 182,563,015–182,589,272 | 7 |
| ENST00000890859 | 182,573,634–182,589,272 | 7 |
| ENST00001144758 | 182,573,634–182,589,272 | 7 |
| ENST00000946546 | 182,573,639–182,589,272 | 7 |
| ENST00000539397 | 182,578,121–182,589,272 | 6 |
顯示 6/6 個蛋白質編碼轉錄本；canonical 優先。
帶型與著絲點依 Ensembl 座標繪製；核染色體長度以 GRCh38 第 1 號染色體為共同尺度。黃色標記表示本基因位置，細小區間加粗以利辨識；實際基因長度與 exon 見下方資料。
分子功能與生物學過程
ribonuclease L 是干擾素（IFN）抗病毒反應的一部分。在 IFN 處理或病毒感染的細胞中，它可能透過多種方式共同限制病毒：直接切割單股病毒 RNA、藉由降解核糖體 RNA（rRNA）抑制蛋白質合成、誘導細胞凋亡，並促使其他抗病毒基因表現。這些作用並非單一途徑，來源描述的是可能共同參與的抗病毒效應。
作為 RNA 切割酶，ribonuclease L 在 UpNp 二核苷酸之後切割 RNA，偏好 UU 與 UA 序列，產生約 4 至 22 個核苷酸長度的離散片段。它也可能在 mRNA 周轉調控中扮演重要角色，但此項功能仍以可能性描述。RNA 切割速率要達到最佳狀態，需要錳或鎂離子。
ribonuclease L 相關的細胞凋亡涉及 JNK 依賴的壓力反應路徑，並可導致粒線體釋放 cytochrome c，進而啟動 caspase 依賴的凋亡。在某些情況下，這種反應可能清除受病毒感染的細胞。它也與自噬和凋亡之間的交互調節有關：小型雙股 RNA 可在較早階段引發自噬作為壓力反應；若壓力持續，則可能在較晚階段促使 caspase 依賴性蛋白水解切割 BECN1，終止自噬並促進凋亡。
此外，ribonuclease L 參與細胞間免疫訊號傳遞。RNA 病毒感染細胞先前產生的 2-5A 可使其在鄰近未感染細胞中受到交叉活化，並觸發第一型干擾素訊號，以限制感染在局部擴散。
Promoter 與基因調控
>RNASEL ENST00000367559 GRCh38 chr1:182589156-182590256 strand=-1 5′→3′ 相對 TSS：-1000 到 +100 bp；1101 bp 依轉錄本 TSS 擷取的基因組序列；TSS = 0，兩端包含，未驗證為 promoter AGGATGAGGGGTGGCCTCCGGGTGATGGTGCCATCTGTGGAGATGGAATAAGTGGGAGGAGGGGCAGATT TAGGAAAAGATGAGTATTTCCATTTGACACATATTCAAGATTTGTAGGTCTAAAGCTCAGCAGAGAGGCT GGGGTTAGAGAGCGAGGCCTGGGAATCCCTGGTGTATAAGGGGTGGTAGAGGCCCCGGGTCTGGATGGTG TGACACAGGTGGTCGTCAAGTGACCATGCACTACTTGTTGTTCACAAGTCCCAGGGCTTTGTCTCCCCAG CAAGACTGGGTATTCTTTGGGGATGGAAATACTTTCCACTACAGCACTAAGTACACAGTACACAGCTCAT TGCTAGGAAGATAGTCAAGAACAGAACTTGTAGAGCAGAAAGGAACCTTCAAAACCAAGTTATAGGAGAG AACTGAGGCCCTACATGGTTAAATCACATGCCTGAGGTCACTCAGCTAAGCAGCCACAGAGCTGGCTGTA GGATCAGGTCTCCAGACTGCCAGTCCGGTACCCTTCTGAGAAGGCCGCACTGCCTCAGAGCTGTGAGTTG AGTGAGCTGAGAAAGGTGACAGGGCTTGGGCTTTGGGCTTACTTAGCTTCTATGAGCCTGCGTTTCATAA TCAACAAGATTGTCAGGGGTTAACTGGGACCATGCTGCATGTAAAGCATTGTGTCTGGAACACAATAGGT GCTCAATATGTGTTTACTTTCCATTCCTTTCTTCCAAGAAGACCAGAATTTGCAATGACAAAGAAAGGAT GCAAGAGTGATGGATGCAGTTGGCTGCTGCCACCTGAAAGGCTGCAAGACTGAGAGGTGAGTGACATGAC CCCGGGCATCACATTCCTCATCAGCAGACAGAAAGTGGCTATTGCTTTCCTCCAGAAGGTGTGCAAGTAG AAGCTTTGCTCCTGGTGCCAGAGTGAGCCTGTGGCTGCTTTCCCTCCCACACTCCTCACTCCTTTCTTGG CTCCGCCCTGCTGACTCAGTGACGCAGCAGGAGGAAACTGCTCGGGCTGCAAGCAGTCTTCCAGGCTTTG CGGCTGCCAAAGGAATAATTGAGACGTCTGAGTTGAGCAGGTAAGGCAGGC
EPDnew 實驗支持 promoter／TSS · 1 筆
| EPDnew ID | TSS（1-based） | 股向 | 來源顯示區間 |
|---|---|---|---|
| RNASEL_1 ↗ | 1:182,589,253 | 負股 | 182,589,243–182,589,302 |
EPDnew human v006 · UCSC hg38，GRCh38/hg38，透過 UCSC 取得。TSS 具有 CAGE／RAMPAGE 等實驗資料支持；任意擷取的上下游區間仍需另行判讀調控功能，不能視為整段皆經功能驗證。
EPD 封存狀態 ↗ · UCSC 資料說明 ↗ · EPD team, SIB Swiss Institute of Bioinformatics; UCSC Genome Browser · CC BY 4.0
查看已取得的調控／motif 註解
ENSR1_CN574 · enhancer · 182588207–182589245 · regulatory
ENSR1_94NGQL · promoter · 182589246–182589746 · regulatory
· motif · 182587974–182587986 · motif
· motif · 182588262–182588271 · motif
· motif · 182588262–182588273 · motif
· motif · 182588488–182588501 · motif
· motif · 182588698–182588707 · motif
· motif · 182588698–182588707 · motif
· motif · 182588872–182588883 · motif
· motif · 182589023–182589032 · motif
· motif · 182589023–182589034 · motif
· motif · 182589414–182589421 · motif
干擾素可促使細胞轉錄編碼抗病毒蛋白的基因，其中包括 2'-5' oligoadenylate synthetases（OASs）。雙股 RNA 刺激 OAS 後，會產生帶有 5'-磷酸基、以 2'-5' 鍵連接的 2-5A；2-5A 的作用是活化 RNASEL。
蛋白質結構域與序列
參考蛋白質長度：741 aa
ribonuclease L 長 741 個胺基酸，屬於 protein kinase 超家族。其蛋白質包含九個 ANK 重複序列、Protein kinase domain（胺基酸 365–586）及 KEN domain（589–723），另有一個 atypical C6-type zinc finger（395–444）。兩段 2-5A binding（P-loop）區域分別位於 229–242 與 253–275；蛋白質第 1–21 與 715–741 個胺基酸則註記為無序區域。
蛋白質三維結構
細胞內定位
ribonuclease L 的定位註記包括細胞質與粒線體；來源未提供定位隨條件改變或異構型差異的說明。
深綠色圓點：來源記載的蛋白質定位；數量不表示含量。
動物細胞結構示意；器官大小與數量不按比例。點選細胞構造可查看定位註解。
交互作用與訊號網絡
拖曳節點後放開可帶動位置變化；點選夥伴查看證據。位置與連線長度不代表結合強度，圖中未推定夥伴彼此之間的關係。
更多交互作用夥伴 · 已取得 1 個夥伴
- IQGAP1P46940 · UniProt INTERACTION · 2 experiments
ribonuclease L 可呈單體或同源二聚體形式；單體被註記為非活性形式。它也與 ABCE1 互作，而此互作會抑制 RNASEL。
疾病與遺傳關聯
RNASEL 相關變異與遺傳性前列腺癌易感性有關，該疾病亦稱 HPC1。此關聯表示變異與疾病易感性相關，來源未將其描述為必然致病的因果關係。前列腺癌多為發生於前列腺導管腺泡的腺癌；約 5% 患者則涉及多種較少見的組織病理類型。
Contextual Functional Evidence Matrix
矩陣以「功能主張」為列，以細胞情境、干預條件、量測結果與證據來源為欄，方便比較同一功能在不同條件下的支持情形。只有含情境與實驗資訊的紀錄會列入矩陣；一般功能註解另列於下方。
功能註解總覽 · 8 筆
| 功能面向 | 功能敘述 | 證據類型 | 可查核來源 |
|---|---|---|---|
| 功能 | RNASEL 是干擾素抗病毒反應中的內切核糖核酸酶；在干擾素處理或病毒感染細胞中，可能藉由切割病毒 RNA、降解 rRNA、誘導凋亡及促進其他抗病毒基因表現發揮作用。它偏好在 UU、UA 序列後切割，並參與細胞間免疫訊號傳遞。 | 含實驗來源 | 證據與來源Endoribonuclease that functions in the interferon (IFN) antiviral response. In INF treated and virus infected cells, RNASEL probably mediates its antiviral effects through a combination of direct cleavage of single-stranded viral RNAs, inhibition of protein synthesis through the degradation of rRNA, induction of apoptosis, and induction of other antiviral genes. RNASEL mediated apoptosis is the result of a JNK-dependent stress-response pathway leading to cytochrome c release from mitochondria and caspase-dependent apoptosis. Therefore, activation of RNASEL could lead to elimination of virus infected cells under some circumstances. In the crosstalk between autophagy and apoptosis proposed to induce autophagy as an early stress response to small double-stranded RNA and at later stages of prolonged stress to activate caspase-dependent proteolytic cleavage of BECN1 to terminate autophagy and promote apoptosis. Might play a central role in the regulation of mRNA turnover. Cleaves 3' of UpNp dimers, with preference for UU and UA sequences, to sets of discrete products ranging from between 4 and 22 nucleotides in length. Involved in intercellular immune signaling. Cross-activated by 2',5'-oligoadenylates (2-5A) previously generated in RNA virus-infected cells, triggers type I interferon signaling in uninfected neighboring cells to limit local spread of infection PMID 11585831 ↗ · PMID 26263979 ↗ · PMID 40010341 ↗ |
| 分子活性 | 錳或鎂是 RNASEL RNA 切割活性達到最佳速率所必需的離子。 | 資料庫紀錄 | |
| 交互作用 | RNASEL 可呈單體或同源二聚體；單體為非活性形式。RNASEL 會與 ABCE1 互作，而此互作具有抑制 RNASEL 的作用。 | 含實驗來源 | 證據與來源Monomer (inactive form) or homodimer. Interacts with ABCE1; this interaction inhibits the RNASEL PMID 15385955 ↗ · PMID 7539425 ↗ |
| 細胞定位 | RNASEL 的細胞內定位包括細胞質與粒線體。 | 含實驗來源 | |
| 調控 | 干擾素促使細胞轉錄抗病毒蛋白基因，包括 OASs；雙股 RNA 刺激 OASs 產生 5'-磷酸化、以 2'-5' 鍵連接的 2-5A，進而活化 RNASEL。 | 資料庫紀錄 | 證據與來源By interferons. Virus replication in higher vertebrates is restrained by IFNs that cause cells to transcribe genes encoding antiviral proteins, such as 2'-5' oligoadenylate synthetases (OASs). oligoadenylate synthetase is stimulated by dsRNA to produce 5'-phosphorylated, 2'-5'-linked oligoadenylates (2-5A), whose function is to activate RNASEL |
| 疾病關聯 | RNASEL 變異與遺傳性前列腺癌易感性相關，疾病名稱為 HPC1。前列腺癌多為發生於前列腺導管腺泡的腺癌，約 5% 患者涉及所列的較罕見組織病理類型；此資料描述的是易感性關聯。 | 推論支持 | 證據與來源Prostate cancer, hereditary, 1 HPC1 A condition associated with familial predisposition to cancer of the prostate. Most prostate cancers are adenocarcinomas that develop in the acini of the prostatic ducts. Other rare histopathologic types of prostate cancer that occur in approximately 5% of patients include small cell carcinoma, mucinous carcinoma, prostatic ductal carcinoma, transitional cell carcinoma, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma (basaloid), signet-ring cell carcinoma and neuroendocrine carcinoma. Disease susceptibility is associated with variants affecting the gene represented in this entry MIM: 601518 PMID 11799394 ↗ · PMID 11941539 ↗ · PMID 12415269 ↗ · PMID 17344846 ↗ |
| 功能 | 研究指出，IFNalpha 可抑制人類 H9 細胞生長，且至少部分是透過 RNase L 降解粒線體 mRNA。細胞中有一部分 RNase L 與其抑制因子 RLI 位於粒線體；以 RNase L 反義 cDNA 或 RLI 正義 cDNA 穩定轉染降低 RNase L 活性後，IFNalpha 不再引起粒線體 mRNA 的轉錄後下調，也未見細胞生長受抑制。 | 文獻摘要 | 證據與來源Interferon alpha (IFNalpha) belongs to a cytokine family that exhibits antiviral properties, immuno-modulating effects, and antiproliferative activity on normal and neoplasic cells in vitro and in vivo. IFNalpha exerts antitumor action by inducing direct cytotoxicity against tumor cells. This toxicity is at least partly due to induction of apoptosis. Although the molecular basis of the inhibition of cell growth by IFNalpha is only partially understood, there is a direct correlation between the sensitivity of cells to the antiproliferative action of IFNalpha and the down-regulation of their mitochondrial mRNAs. Here, we studied the role of the 2-5A/RNase L system and its inhibitor RLI in this regulation of the mitochondrial mRNAs by IFNalpha. We found that a fraction of cellular RNase L and RLI is localized in the mitochondria. Thus, we down-regulated RNase L activity in human H9 cells by stably transfecting (i) RNase L antisense cDNA or (ii) RLI sense cDNA constructions. In contrast to control cells, no post-transcriptional down-regulation of mitochondrial mRNAs and no cell growth inhibition were observed after IFNalpha treatment in these transfectants. These results demonstrate that IFNalpha exerts its antiproliferative effect on H9 cells at least in part via the degradation of mitochondrial mRNAs by RNase L. PMID 11585831 ↗The 2-5A/RNase L/RNase L inhibitor (RLI) [correction of (RNI)] pathway regulates mitochondrial mRNAs stability in interferon alpha-treated H9 cells. · cc by |
| 功能 | 研究指出，RNase L 產生的小型雙股 RNA 可促使自噬轉向細胞凋亡：caspase 切割 Beclin-1，終止自噬；其 C 端片段與促凋亡蛋白 Bax 移至粒線體，促使 cytochrome C 釋放至細胞質。表現抗 caspase 切割的 Beclin-1 可抑制凋亡並維持自噬；抑制 RNase L 誘導的自噬會促進細胞死亡，而抑制凋亡則延長自噬。 | 文獻摘要 | 證據與來源Autophagy and apoptosis share regulatory molecules enabling crosstalk in pathways that affect cellular homeostasis including response to viral infections and survival of tumor cells. Ribonuclease L (RNase L) is an antiviral endonuclease that is activated in virus-infected cells and cleaves viral and cellular single-stranded RNAs to produce small double-stranded RNAs with roles in amplifying host responses. Activation of RNase L induces autophagy and apoptosis in many cell types. However, the mechanism by which RNase L mediates crosstalk between these two pathways remains unclear. Here we show that small dsRNAs produced by RNase L promote a switch from autophagy to apoptosis by caspase-mediated cleavage of Beclin-1, terminating autophagy. The caspase 3-cleaved C-terminal fragment of Beclin-1 enhances apoptosis by translocating to the mitochondria along with proapoptotic protein, Bax, and inducing release of cytochrome C to the cytosol. Cleavage of Beclin-1 determines switch to apoptosis since expression of caspase-resistant Beclin-1 inhibits apoptosis and sustains autophagy. Moreover, inhibiting RNase L-induced autophagy promotes cell death and inhibiting apoptosis prolongs autophagy in a cross-inhibitory mechanism. Our results demonstrate a novel role of RNase L generated small RNAs in cross-talk between autophagy and apoptosis that impacts the fate of cells during viral infections and cancer. PMID 26263979 ↗RNase L Cleavage Products Promote Switch from Autophagy to Apoptosis by Caspase-Mediated Cleavage of Beclin-1. · cc by |
核酸與蛋白質序列
GACGCAGCAGGAGGAAACTGCTCGGGCTGCAAGCAGTCTT40CCAGGCTTTGCGGCTGCCAAAGGAATAATTGAGACGTCTG80AGTTGAGCAGGTGGAATGTCAGAAGACTGAGAACATTGTT120CCTTCTTCATACTGCTGCTCTGTTGCCAGAGAATCCCAAT160TTACACTCAAAGCTTCTTTGATTAAGTGCTAGGAGATAAA200TTTGCATTTTCTCAAGGAAAAGGCTAAAAGTGGTAGCAGG240TGGCATTTACCGTCATGGAGAGCAGGGATCATAACAACCC280CCAGGAGGGACCCACGTCCTCCAGCGGTAGAAGGGCTGCA320GTGGAAGACAATCACTTGCTGATTAAAGCTGTTCAAAACG360AAGATGTTGACCTGGTCCAGCAATTGCTGGAAGGTGGAGC400CAATGTTAATTTCCAGGAAGAGGAAGGGGGCTGGACACCT440CTGCATAACGCAGTACAAATGAGCAGGGAGGACATTGTGG480AACTTCTGCTTCGTCATGGTGCTGACCCTGTTCTGAGGAA520GAAGAATGGGGCCACGCCTTTTATCCTCGCAGCGATTGCG560GGGAGCGTGAAGCTGCTGAAACTTTTCCTTTCTAAAGGAG600CAGATGTCAATGAGTGTGATTTTTATGGCTTCACAGCCTT640CATGGAAGCCGCTGTGTATGGTAAGGTCAAAGCCCTAAAA680TTCCTTTATAAGAGAGGAGCAAATGTGAATTTGAGGCGAA720AGACAAAGGAGGATCAAGAGCGGCTGAGGAAAGGAGGGGC760CACAGCTCTCATGGACGCTGCTGAAAAAGGACACGTAGAG800GTCTTGAAGATTCTCCTTGATGAGATGGGGGCAGATGTAA840ACGCCTGTGACAATATGGGCAGAAATGCCTTGATCCATGC880TCTCCTGAGCTCTGACGATAGTGATGTGGAGGCTATTACG920CATCTGCTGCTGGACCATGGGGCTGATGTCAATGTGAGGG960cDNA 使用 DNA 字母 T；mRNA 模式改以 U 顯示。轉錄本保留已註解的非編碼區，未另外加入 poly(A) 尾；非編碼 RNA 的參考轉錄本也可能仍需後續加工。數字為所選序列的 1-based 位置。長序列以黃色捲軸瀏覽，可複製或下載完整轉錄本與蛋白質；基因組 DNA 隨捲動取得所需範圍。