SPATA2 promotes CYLD activity and regulates TNF-induced NF-κB signaling and cell death
SPATA2 promotes CYLD activity and regulates TNF-induced NF-κB signaling and cell death
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DOI：
10.15252/embr.201642592
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发表时间：
2016-10-01
期刊：
影响因子：
7.7
通讯作者：
Maurer, Ulrich
中科院分区：
文献类型：
--
作者：
Schlicher, Lisa;Wissler, Manuela;Maurer, Ulrich
K63 和 Met1 连接的泛素化是 TNF 受体信号转导的关键翻译后修饰。这些非降解性泛素化被去泛素酶 (DUB)（例如 CYLD 酶）抵消，从而产生适当的信号强度，但这一过程的调节仍不完全清楚。在这里，我们描述了 CYLD 的相互作用伙伴 SPATA2，我们通过质谱筛选鉴定了它。我们发现 SPATA2 通过其 PUB 结构域与 CYLD 相互作用，而 SPATA2 的 PUB 相互作用基序 (PIM) 与 LUBAC 组件 HOIP 的 PUB 结构域相互作用。 SPATA2 是 TNFR 刺激后 CYLD 募集至 TNF 受体信号复合物所必需的。此外，SPATA2 充当 CYLD 的 K63 和 M1 去泛素酶活性的变构激活剂。因此，SPATA2 显着减弱 TNF 诱导的 NF-κ B 和 MAPK 信号传导。相反，SPATA2 是 TNF 诱导的复合物 II 形成、半胱天冬酶激活和细胞凋亡所必需的。因此，本研究确定 SPATA2 是 TNF 信号通路中的一个重要因子，对于细胞因子介导的作用具有重要作用。
K63- and Met1-linked ubiquitylation are crucial posttranslational modifications for TNF receptor signaling. These non-degradative ubiquitylations are counteracted by deubiquitinases (DUBs), such as the enzyme CYLD, resulting in an appropriate signal strength, but the regulation of this process remains incompletely understood. Here, we describe an interaction partner of CYLD, SPATA2, which we identified by a mass spectrometry screen. We find that SPATA2 interacts via its PUB domain with CYLD, while a PUB interaction motif (PIM) of SPATA2 interacts with the PUB domain of the LUBAC component HOIP. SPATA2 is required for the recruitment of CYLD to the TNF receptor signaling complex upon TNFR stimulation. Moreover, SPATA2 acts as an allosteric activator for the K63- and M1-deubiquitinase activity of CYLD. In consequence, SPATA2 substantially attenuates TNF-induced NF-kappa B and MAPK signaling. Conversely, SPATA2 is required for TNF-induced complex II formation, caspase activation, and apoptosis. Thus, this study identifies SPATA2 as an important factor in the TNF signaling pathway with a substantial role for the effects mediated by the cytokine.