HSPA13 facilitates NF-κB–mediated transcription and attenuates cell death responses in TNFα signaling
Chun Gao, Jianhua Deng, Hanchenxi Zhang, Xinran Li, Shuchen Gu, Mingjie Zheng, Mei Tang, Yezhang Zhu, Xin Lin, Jianping Jin, Long Zhang, Jun Huang, Jian Zou, Zongping Xia, Pinglong Xu, Li Shen, Bin Zhao, Xin‐Hua Feng
Abstract
RIP1 has emerged as a master regulator in TNFα signaling that controls two distinct cellular fates: cell survival versus programmed cell death. Because the default response of most cells to TNFα is NF-κB–mediated inflammation and survival, a specific mechanism must exist to control the divergence of signaling outcome. Here, we identify HSPA13 as a transcription-independent checkpoint to modulate the role of RIP1 in TNFα signaling. Through specific binding to TNFR1 and RIP1, HSPA13 enhances TNFα-induced recruitment of RIP1 to TNFR1, and consequently promotes downstream NF-κB transcriptional responses. Meanwhile, HSPA13 attenuates the participation of RIP1 in cytosolic complex II and prevents cells from programmed death. Loss of HSPA13 shifts the transition of RIP1 from complex I to complex II and promotes both apoptosis and necroptosis. Thus, our study provides compelling evidence for the cellular protective function of HSPA13 in fine-tuning TNFα responses.