基因總覽
TRAF6（TNF receptor associated factor 6）是蛋白質編碼基因，產物屬 TNF receptor-associated factor 家族。這種蛋白質兼具接頭蛋白與 E3 ubiquitin ligase 的性質，能參與受體訊號傳遞，並調節下游訊號反應。其結構包含 RING-type zinc finger、兩個 TRAF-type zinc finger，以及 MATH domain；這些結構特色構成蛋白質的不同區域。
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 |
|---|---|---|
| ENST00000526995 ★ | 36,483,769–36,510,272 | 7 |
| ENST00000348124 | 36,483,769–36,510,308 | 8 |
| ENST00000876419 | 36,483,769–36,510,308 | 5 |
| ENST00000876420 | 36,483,769–36,510,308 | 6 |
| ENST00001144198 | 36,483,769–36,510,308 | 7 |
| ENST00000876418 | 36,487,853–36,510,308 | 7 |
| ENST00001130894 | 36,496,685–36,510,308 | 4 |
| ENST00001112752 | 36,497,904–36,510,308 | 3 |
| ENST00001098456 | 36,500,504–36,510,308 | 3 |
顯示 9/9 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
TRAF6 的 E3 ubiquitin ligase 活性與 UBE2N、UBE2V1 協同，促成連接至受體蛋白的 Lys-63-linked polyubiquitin chains，已知受體包括 ECSIT、IKBKG、IRAK1、AKT1 與 AKT2。它也能促成游離、未錨定的 polyubiquitin chain 泛素化，並由此引發 MAP3K7 活化。這些泛素化事件與 NF-kappa-B、JUN 的活化相關；TRAF6 也可透過泛素化 LAT 參與 TCR 訊號傳遞。
在訊號調節上，TRAF6 可啟動 Lys-63 與 Lys-48 混合分支的泛素鏈組裝：先形成 Lys-63-linked polyubiquitin chains，再由 HUWE1 加上 Lys-48-linked 分支。此分支鏈可被 TAB2 辨識，並保護 Lys-63 連結免受 CYLD 去泛素化，進而調節 JNK 與 NF-kappa-B 訊號路徑。
TRAF6 作為接頭蛋白，似乎參與 TNF receptor、IL-1 receptor 與 IL-17 receptor 啟動的訊號傳遞。受到 RANK-L 刺激時，它可透過促進 adapter protein complex 1（AP-1）與 NF-kappa-B 活化，調節破骨細胞分化。它也與 MAP3K8 協同傳遞 CD40 訊號，在 B 細胞及巨噬細胞中活化 ERK，因此可能參與免疫球蛋白產生的調節。
其他功能包括在 B 淋巴球中抑制 c-Myb 介導的轉錄活化；來源亦指出，TRAF6 似乎參與樹突細胞成熟及／或活化。這些作用顯示 TRAF6 可透過泛素化與接頭功能，參與多種受體路徑及細胞反應，但部分功能仍以相似性推論描述。
Promoter 與基因調控
>TRAF6 ENST00000526995 GRCh38 chr11:36510172-36511272 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 TATGTTGCCCAGGCTGGTCTCAAATTCCTGGCCTCAAGTGATCCTCCTGCCTTAGCCTCCCAAAGTACTG GGATTATAGGCATGAGCCTATTTGTGCCTGGCCAGATAGTTTTAAATAATTTCTTTACATATTTTATCTC ATCCTTCCAACAACCCTGTGAGGTAGATACTATTATTATCCCCATGTTAATACGAGATGAGAAAACTGAA ACAAGTACAGATTAAGTATTTTACCTGAATCACACATTTATTGTAGGAAAAACCGGATTGGAACCAAGCA TTCTGGCTTCAGGATACATACGCATGACTACTATCCTGGAAAACCTCCCCTAAGAGGTGGACGATGAACC AAATATGCAGAGGTGGATGAAACTCTTTTGTGCTTCTCCAGCAAAACGCGTGGTACATTCTCTAGACGTT TATGACCAGTTAAACAGGGAATTTAAAATAGTTTTCCCATGACAGAGAAAGACAAAGCGCTGGTGTTCTT GGCAGGAAATTCAAAGAAATATTTAAGGCAAGGGCTGACTCCCTTGGACCGGATGAAGGGGAAGAGCAGG TAATAATAGAGGGTTCTATGGATCGCAGAAACTTCCTGGGCAAGGAGGGTGGAGCTGGGGAGGGGTTTAA GAATTCCTGAAGGTCAAGCGATCTAGCCCAGCTGGGGTTTTCTCCTGCTTGGAGAGGGGTGCTATAAAAG CGCAGTTTGGGATTACTACTGTCGCCACTGCTCACCAAATTAAGTTATTCCGGGAGGGATCTTCTCGTCG CCATCCTCATTCCAACACACACCCATTGACACACTCGGGTTCGGCTGTGCGGTGCAACGAATTCCCAGGT GGGACACCCGAGCAGGAAGAAAGCCAGGCTGCGGGGCTGGGGGCGCCGCCCGGCCCGCGCCACAGTCCGC CTGGAGGATCACCGCCAGGGGGCACTCTCTCCGAACTCGGCCGCTCTGTCTCCTCCCCGGCGCGCTCCCT GCCCCTCGCTCCCCGCAGCCAGCAGAGAAGGCGGAAGCAGTGGCGTCCGCAGCTGGGGCTTGGCCTGCGG GCGGCCAGCGAAGGTGGCGAAGGCTCCCACTGGATCCAGAGTTTGCCGTCC
EPDnew 實驗支持 promoter／TSS · 1 筆
| EPDnew ID | TSS（1-based） | 股向 | 來源顯示區間 |
|---|---|---|---|
| TRAF6_1 ↗ | 11:36,510,269 | 負股 | 36,510,259–36,510,318 |
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
ENSR11_C5LS2 · enhancer · 36508679–36510245 · regulatory
ENSR11_5BKT9D · CTCF_binding_site · 36509906–36509927 · regulatory
ENSR11_5BKT9T · CTCF_binding_site · 36510012–36510036 · regulatory
ENSR11_833ZJM · promoter · 36510246–36510413 · regulatory
ENSR11_5BKTCD · CTCF_binding_site · 36510335–36510356 · regulatory
ENSR11_B98M7 · enhancer · 36510414–36511026 · regulatory
· motif · 36508282–36508291 · motif
· motif · 36508282–36508291 · motif
· motif · 36509479–36509490 · motif
· motif · 36509697–36509710 · motif
· motif · 36509702–36509714 · motif
· motif · 36509704–36509711 · motif
· motif · 36509704–36509717 · motif
· motif · 36509908–36509924 · motif
· motif · 36510014–36510030 · motif
· motif · 36510017–36510033 · motif
· motif · 36510254–36510265 · motif
· motif · 36510254–36510265 · motif
· motif · 36510337–36510353 · motif
· motif · 36510430–36510439 · motif
· motif · 36510534–36510545 · motif
蛋白質結構域與序列
參考蛋白質長度：522 aa
TRAF6 蛋白質長 522 個胺基酸，屬 TNF receptor-associated factor 家族。其 N 端含 RING-type zinc finger（第 70–109 位），另有 TRAF-type 1 與 TRAF-type 2 zinc finger（第 150–202 位及第 203–259 位）；C 端區域含 MATH domain（第 350–499 位）。來源亦標示 N 端第 1–354 位與 TAX1BP1 互作、C 端第 355–522 位與 TANK 互作的區域。
蛋白質三維結構
細胞內定位
TRAF6 可見於細胞質、細胞皮質與細胞核；部分侵襲性 B 細胞淋巴瘤細胞株，以及靜止或活化的 T、B 淋巴球中，均觀察到核內 TRAF6，並可出現在點狀核內蛋白質複合體。 泛素化可能發生於細胞質，sumoylation 則可能發生於細胞核；RSAD2/viperin 可招募 TRAF6 至脂滴，此定位關係為相似性推論。
深綠色圓點：來源記載的蛋白質定位；數量不表示含量。
未繪示構造：Lipid droplet。這些構造未在通用細胞圖中標點，仍保留來源定位名稱。
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 55 個夥伴
- AMBRA1Q9C0C7-3 · UniProt INTERACTION · 2 experiments
- BRSK2Q8IWQ3-3 · UniProt INTERACTION · 3 experiments
- CD40P25942 · UniProt INTERACTION · 2 experiments
- EDA2RQ9HAV5 · UniProt INTERACTION · 3 experiments
- EDARADDQ8WWZ3 · UniProt INTERACTION · 5 experiments
- IL1R1P14778 · UniProt INTERACTION · 2 experiments
- IQUBQ8NA54 · UniProt INTERACTION · 3 experiments
- IRAK1P51617 · UniProt INTERACTION · 3 experiments
- IRAK2O43187 · UniProt INTERACTION · 4 experiments
- IRAK3Q9Y616 · UniProt INTERACTION · 3 experiments
- LNX1Q8TBB1 · UniProt INTERACTION · 3 experiments
- MALT1Q9UDY8 · UniProt INTERACTION · 5 experiments
- MAP3K7O43318 · UniProt INTERACTION · 2 experiments
- MAVSQ7Z434 · UniProt INTERACTION · 4 experiments
- MEOX2P50222 · UniProt INTERACTION · 3 experiments
- MTURNQ8N3F0 · UniProt INTERACTION · 3 experiments
- OTUB2Q96DC9 · UniProt INTERACTION · 3 experiments
- PLEKHF2Q9H8W4 · UniProt INTERACTION · 3 experiments
- POLIQ9UNA4 · UniProt INTERACTION · 3 experiments
- RAD23AP54725 · UniProt INTERACTION · 3 experiments
- RUSC1Q9BVN2-2 · UniProt INTERACTION · 2 experiments
- S100BP04271 · UniProt INTERACTION · 3 experiments
- SPHK1Q9NYA1 · UniProt INTERACTION · 2 experiments
- SQSTM1Q13501 · UniProt INTERACTION · 4 experiments
- SYKP43405-2 · UniProt INTERACTION · 3 experiments
TRAF6 可形成同源三聚體及同源寡聚體；來源指出其 N 端區域為二聚、C 端區域為三聚，可能提供寡聚化方式。IL1B 處理後，TRAF6 與 PELI1、IRAK1、IRAK4、MYD88 形成複合體，進而招募 MAP3K7/TAK1、TAB1、TAB2，介導 NF-kappa-B 活化；SMAD6 直接結合 PELI1 可阻止此複合體形成。TRAF6 也結合 CD40、RANK、IL17R，並與多種訊號蛋白互作。TAX1BP1 互作可促進 TRAF6 去泛素化並抑制 NF-kappa-B 活化；病毒感染時與 STING1 的互作則促進 NF-kappa-B 訊號活化。
疾病與遺傳關聯
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 · 5 筆
| 功能面向 | 功能敘述 | 證據類型 | 可查核來源 |
|---|---|---|---|
| 功能 | TRAF6 與 UBE2N、UBE2V1 協同形成 Lys-63-linked polyubiquitin chains，也能促進游離泛素鏈泛素化及 MAP3K7 活化，進而關聯 NF-kappa-B、JUN 與 JNK 訊號。它參與多種受體路徑、破骨細胞分化、TCR 訊號及免疫細胞功能；樹突細胞作用以相似性推論描述。 | 含實驗來源 | 證據與來源E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as ECSIT, IKBKG, IRAK1, AKT1 and AKT2. Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation. Leads to the activation of NF-kappa-B and JUN. Seems to also play a role in dendritic cells (DCs) maturation and/or activation (By similarity). Represses c-Myb-mediated transactivation, in B-lymphocytes. Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor. Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation (By similarity). Together with MAP3K8, mediates CD40 signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production (By similarity). Acts as a regulator of the JNK and NF-kappa-B signaling pathways by initiating assembly of heterotypic 'Lys-63'-/'Lys-48'-linked branched ubiquitin chains that are then recognized by TAB2: TRAF6 catalyzes initial 'Lys-63'-linked-polyubiquitin chains that are then branched via 'Lys-48'-linked polyubiquitin by HUWE1. 'Lys-63'-/'Lys-48'-linked branched ubiquitin chains protect 'Lys-63'-linkages from CYLD deubiquitination. Participates also in the TCR signaling by ubiquitinating LAT PMID 11057907 ↗ · PMID 12140561 ↗ · PMID 16378096 ↗ · PMID 17135271 ↗ · PMID 17703191 ↗ · PMID 18093978 ↗ · PMID 18347055 ↗ · PMID 18758450 ↗ · PMID 19465916 ↗ · PMID 19675569 ↗ · PMID 19713527 ↗ · PMID 19825828 ↗ · PMID 23514740 ↗ · PMID 25907557 ↗ · PMID 27746020 ↗ · PMID 31620128 ↗ · PMID 34490261 ↗ · PMID 39920527 ↗ · PMID 40973797 ↗ · PMID 41747053 ↗ · PMID 8837778 ↗ |
| 分子活性 | S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine. | 含實驗來源 | 證據與來源S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine. PMID 17135271 ↗ · PMID 19713527 ↗ · PMID 23514740 ↗ · PMID 27746020 ↗ · PMID 34490261 ↗ |
| 分子活性 | 此註記將 TRAF6 的酵素相關功能歸為蛋白質修飾，並特別列出蛋白質泛素化；未提供額外的反應條件、細胞系統或功能結果。 | 資料庫紀錄 | |
| 交互作用 | TRAF6 可形成同源寡聚體，並在 IL1B 處理後與 PELI1、IRAK1、IRAK4、MYD88 組成招募 MAP3K7、TAB1、TAB2 的複合體。來源另記載多種直接結合或互作，包括 CD40、RANK、TAX1BP1 與 STING1，並描述部分互作的訊號結果。 | 含實驗來源 | 證據與來源Homotrimer. Homooligomer. N-terminal region is dimeric while C-terminal region is trimeric; maybe providing a mode of oligomerization. Upon IL1B treatment, forms a complex with PELI1, IRAK1, IRAK4 and MYD88; this complex recruits MAP3K7/TAK1, TAB1 and TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1 prevents the complex formation and hence negatively regulates IL1R-TLR signaling and eventually NF-kappa-B-mediated gene expression. Binds to TNFRSF5/CD40 and TNFRSF11A/RANK. Associates with NGFR, TNFRSF17, IRAK2, IRAK3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting protein TRIP and TNF receptor associated protein TDP2. Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ (By similarity). Interacts with PELI2 and PELI3. Binds UBE2V1. Interacts with TAX1BP1; this interaction mediates deubiquitination of TRAF6 and inhibition of NF-kappa-B activation. Interacts with ZNF675. Interacts with ARRB1 and ARRB2. Interacts with MAP3K7 and TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with UBE2N. Interacts with TGFBR1, HDAC1 and RANGAP1. Interacts with AKT1, AKT2 and AKT3. Interacts (via TRAF domains) with NUMBL (via C-terminal). Interacts with RBCK1. Interacts with LIMD1 (via LIM domains) (By similarity). Interacts with RSAD2/viperin (By similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the kinase catalytic domain) (By similarity). Interacts with ZFAND5. Interacts with IL1RL1. Interacts with TRAFD1. Interacts with AJUBA. Interacts with MAVS/IPS1. Interacts (via TRAF domains) with DYNC2I2 (via WD domains). Interacts with IFIT3 (via N-terminus). Interacts with TICAM2. Interacts with CARD14. Interacts with CD40 and MAP3K8; the interaction is required for ERK activation (By similarity). Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1. Interacts with TANK; this interaction increases in response to DNA damage. Interacts with USP10; this interaction increases in response to DNA damage. Interacts with ZC3H12A; this interaction increases in response to DNA damage and is stimulated by TANK. Interacts with WDFY3 (By similarity). Interacts with TRIM13. Interacts with GPS2 (By similarity). Interacts (via C-terminus) with SASH1. Interacts with LRRC19. Interacts with IL17RA and TRAF3IP2. Interacts with TOMM70. Interacts with AMBRA1; interaction is required to mediate 'Lys-63'-linked ubiquitination of ULK1. Interacts with CRBN; this interaction inhibits TLR4-mediated signaling by preventing TRAF6-mediated ubiquitination of ECSIT. Interacts with STING1; interaction takes place in response to virus infection and promotes activation of NF-kappa-B signaling. Interacts with ZDHHC11; this interaction increases TRAF6 E3 ligase activity PMID 10920205 ↗ · PMID 17703191 ↗ · PMID 19825828 ↗ · PMID 20628368 ↗ · PMID 23524951 ↗ · PMID 23776175 ↗ · PMID 25026888 ↗ · PMID 25736436 ↗ · PMID 25861989 ↗ · PMID 28087809 ↗ · PMID 31620128 ↗ · PMID 34490261 ↗ · PMID 40973797 ↗ |
| 細胞定位 | TRAF6 位於細胞質、細胞皮質、細胞核與脂滴；部分淋巴細胞及侵襲性 B 細胞淋巴瘤細胞株可見核內 TRAF6，且其存在於點狀核內蛋白質複合體。泛素化可能發生於細胞質、sumoylation 可能發生於細胞核；RSAD2/viperin 招募 TRAF6 至脂滴的描述屬相似性推論。 | 含實驗來源 | 證據與來源Cytoplasm; Cytoplasm, cell cortex; Nucleus; Lipid droplet; Found in the nuclei of some aggressive B-cell lymphoma cell lines as well as in the nuclei of both resting and activated T- and B-lymphocytes. Found in punctate nuclear body protein complexes. Ubiquitination may occur in the cytoplasm and sumoylation in the nucleus. RSAD2/viperin recruits it to the lipid droplet (By similarity) PMID 18093978 ↗ · PMID 23514740 ↗ · PMID 24586164 ↗ · PMID 39920527 ↗ |
核酸與蛋白質序列
AGCAGAGAAGGCGGAAGCAGTGGCGTCCGCAGCTGGGGCT40TGGCCTGCGGGCGGCCAGCGAAGGTGGCGAAGGCTCCCAC80TGGATCCAGAGTTTGCCGTCCAAGCAGCCTCGTCTCGGCG120CGCAGTGTCTGTGTCCGTCCTCTACCAGCGCCTTGGCTGA160GCGGAGTCGTGCGGTTGGTGGGGGAGCCCTGCCCTCCTGG200TTCGGCCTCCCCGCGCACTAGAACGAGCAAGTGATAATCA240AGTTACTATGAGTCTGCTAAACTGTGAAAACAGCTGTGGA280TCCAGCCAGTCTGAAAGTGACTGCTGTGTGGCCATGGCCA320GCTCCTGTAGCGCTGTAACAAAAGATGATAGTGTGGGTGG360AACTGCCAGCACGGGGAACCTCTCCAGCTCATTTATGGAG400GAGATCCAGGGATATGATGTAGAGTTTGACCCACCCCTGG440AAAGCAAGTATGAATGCCCCATCTGCTTGATGGCATTACG480AGAAGCAGTGCAAACGCCATGCGGCCATAGGTTCTGCAAA520GCCTGCATCATAAAATCAATAAGGGATGCAGGTCACAAAT560GTCCAGTTGACAATGAAATACTGCTGGAAAATCAACTATT600TCCAGACAATTTTGCAAAACGTGAGATTCTTTCTCTGATG640GTGAAATGTCCAAATGAAGGTTGTTTGCACAAGATGGAAC680TGAGACATCTTGAGGATCATCAAGCACATTGTGAGTTTGC720TCTTATGGATTGTCCCCAATGCCAGCGTCCCTTCCAAAAA760TTCCATATTAATATTCACATTCTGAAGGATTGTCCAAGGA800GACAGGTTTCTTGTGACAACTGTGCTGCATCAATGGCATT840TGAAGATAAAGAGATCCATGACCAGAACTGTCCTTTGGCA880AATGTCATCTGTGAATACTGCAATACTATACTCATCAGAG920AACAGATGCCTAATCATTATGATCTAGACTGCCCTACAGC960cDNA 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。