Department of Pharmacology and Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea.
Biotechnology Process Engineering Center, Korea Research Institute of Bioscience & Biotechnology, Cheongju, 28116, Republic of Korea.
Cell Death Differ. 2022 Jun;29(6):1152-1163. doi: 10.1038/s41418-021-00906-9. Epub 2021 Nov 27.
In TNF signaling, ubiquitination of RIP1 functions as an early cell-death checkpoint, which prevents the spatial transition of the signaling complex from complex-I to death-inducing complex-II. Here, we report that ankyrin repeat domain 13a (ANKRD13a) acts as a novel component of complex-II to set a higher signal threshold for the cytotoxic potential of TNF. ANKRD13a deficiency is sufficient to turn the response to TNF from survival to death by promoting the formation of complex-II without affecting NF-κB activation. ANKRD13a binds to ubiquitinated-RIP1 via its UIM, and subsequently limits the association of FADD and caspase-8 with RIP1. Moreover, high ANKRD13a expression is inversely correlated with apoptotic phenotypes in ovarian cancer tissues and is associated with poor prognosis. Our work identifies ANKRD13a as a novel gatekeeper of the early cell-death checkpoint, which may function as part of an escape mechanism from cell death in some cancers.
在 TNF 信号转导中，RIP1 的泛素化作为早期细胞死亡的检查点，阻止信号复合物从复合物-I 向诱导死亡的复合物-II 的空间转移。在这里，我们报告锚蛋白重复域 13a (ANKRD13a) 作为复合物-II 的一个新组件，为 TNF 的细胞毒性潜力设定更高的信号阈值。ANKRD13a 缺陷足以通过促进复合物-II 的形成将对 TNF 的反应从存活转变为死亡，而不影响 NF-κB 的激活。ANKRD13a 通过其 UIM 与泛素化的 RIP1 结合，随后限制 FADD 和 caspase-8 与 RIP1 的结合。此外，卵巢癌组织中高表达 ANKRD13a 与凋亡表型呈负相关，并与预后不良相关。我们的工作确定 ANKRD13a 作为早期细胞死亡检查点的新型门控因子，它可能作为某些癌症中逃避细胞死亡的机制的一部分发挥作用。
