SNX27-driven membrane localisation of OTULIN antagonises linear ubiquitination and NF-κB signalling activation.
SNX27-driven membrane localisation of OTULIN antagonises linear ubiquitination and NF-κB signalling activation.
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SNX27 驱动的 OTULIN 膜定位拮抗线性泛素化和 NF-kappa B 信号激活
DOI：
10.1186/s13578-021-00659-5
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发表时间：
2021-07-27
影响因子：
7.5
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Shi R;Shi X;Qin D;Tang S;Vermeulen M;Zhang X
线性泛素化是一种新型的泛素化，在肿瘤坏死因子（TNF）信号转导等信号通路中发挥重要的生理作用。然而，除了已被广泛描述的酶调节剂E3连接酶线性泛素链组装复合物（LUBAC）和去泛素化酶OTULIN外，对线性泛素化的调节机制知之甚少。在此之前，我们在基于质谱的泛素相互作用筛选中鉴定了SNX 27，一种分选连接蛋白家族蛋白，作为选择性线性泛素链相互作用物。在这里，我们证明了线性泛素链和SNX 27之间的相互作用是由OTULIN介导的。此外，我们发现SNX 27抑制LUBAC介导的线性泛素链形成和TNFα诱导的信号传导激活。机制研究表明，在TNFα刺激后，OTULIN-SNX 27定位于膜相关TNF受体复合物，其中OTULIN去泛素化由LUBAC复合物形成的线性聚泛素链。值得注意的是，霍乱毒素对SNX 27-逆转录体易位的化学抑制抑制了OTULIN膜定位。总之，我们的研究表明，SNX 27通过促进OTULIN定位于TNF受体复合物来抑制TNFα诱导的NF-κB信号传导激活。在线版本包含补充材料，可通过10.1186/s13578-021-00659-5获得。
Linear ubiquitination is a novel type of ubiquitination that plays important physiological roles in signalling pathways such as tumour necrosis factor (TNF) signalling. However, little is known about the regulatory mechanisms of linear ubiquitination, except the well-described enzymatic regulators E3 ligase linear ubiquitin chain assembly complex (LUBAC) and deubiquitinase OTULIN. Previously, we identified SNX27, a member of the sorting nexin family protein, as a selective linear ubiquitin chain interactor in mass spectrometry-based ubiquitin interaction screening. Here, we demonstrated that the interaction between the linear ubiquitin chain and SNX27 is mediated by the OTULIN. Furthermore, we found that SNX27 inhibits LUBAC-mediated linear ubiquitin chain formation and TNFα-induced signalling activation. Mechanistic studies showed that, upon TNFα stimulation, OTULIN-SNX27 is localised to membrane-associated TNF receptor complex, where OTULIN deubiquitinates the linear polyubiquitin chain that formed by the LUBAC complex. Significantly, chemical inhibition of SNX27-retromer translocation by cholera toxin inhibits OTULIN membrane localization. In conclusion, our study demonstrated that SNX27 inhibits TNFα induced NF-κB signalling activation via facilitating OTULIN to localize to TNF receptor complex. The online version contains supplementary material available at 10.1186/s13578-021-00659-5.
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影响因子：
3.3
作者：
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64.8
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通讯作者：
Dikic, Ivan