Phosphorylation of caspase-8 by RSKs via organ-constrained effects controls the sensitivity to TNF-induced death

Peng He; Tingting Ai; Muzhen Qiao; Zhang-Hua Yang; Jiahuai Han

doi:10.1038/s41420-024-02024-0

Phosphorylation of caspase-8 by RSKs via organ-constrained effects controls the sensitivity to TNF-induced death

Cell Death Discov. 2024 May 24;10(1):255. doi: 10.1038/s41420-024-02024-0.

Authors

Peng He¹, Tingting Ai², Muzhen Qiao², Zhang-Hua Yang^{3

4}, Jiahuai Han^{5

6

7}

Affiliations

¹ Research Unit of Cellular Stress of CAMS, Xiang'an Hospital of Xiamen University, Cancer Research Center of Xiamen University, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China.
² State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China.
³ Research Unit of Cellular Stress of CAMS, Xiang'an Hospital of Xiamen University, Cancer Research Center of Xiamen University, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China. zhanghuayang@zju.edu.cn.
⁴ Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310012, China. zhanghuayang@zju.edu.cn.
⁵ Research Unit of Cellular Stress of CAMS, Xiang'an Hospital of Xiamen University, Cancer Research Center of Xiamen University, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China. jhan@xmu.edu.cn.
⁶ State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China. jhan@xmu.edu.cn.
⁷ Laboratory Animal Center, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, 361102, China. jhan@xmu.edu.cn.

Abstract

Caspase-8 (Casp8) serves as an initiator of apoptosis or a suppressor of necroptosis in context-dependent manner. Members of the p90 RSK family can phosphorylate caspase-8 at threonine-265 (T265), which can inactivate caspase-8 for bypassing caspase-8-mediated blockade of necroptosis and can also decrease caspase-8 level by promoting its degradation. Mutating T265 in caspase-8 to alanine (A) in mice blocked TNF-induced necroptotic cecum damage but resulted in unexpectedly massive injury in the small intestine. Here, we show RSK1, RSK2, and RSK3 redundantly function in caspase-8 phosphorylation, and the duodenum is the most severely affected part of the small intestine when T265 phosphorylation of caspase-8 was prevented. Eliminating caspase-8 phosphorylation resulted in a duodenum-specific increase in basal caspase-8 protein level, which shall be responsible for the increased sensitivity to TNF-induced damage. Apoptosis of intestinal epithelial cells (IECs) was predominant in the duodenum of TNF-treated Rsk1^-^/^-Rsk2^-^/^-Rsk3^-^/^- and Casp8^T265A/T265A mice, though necroptosis was also observed. The heightened duodenal injury amplified systemic inflammatory responses, as evidenced by the contribution of hematopoietic cells to the sensitization of TNF-induced animal death. Further analysis revealed that hematopoietic and non-hematopoietic cells contributed differentially to cytokine production in response to the increased cell death. Collectively, RSKs emerges as a previously overlooked regulator that, via tissue/organ-constrained inactivating caspase-8 and/or downregulating caspase-8 protein level, controls the sensitivity to TNF-induced organ injury and animal death.