Crucial Roles of the RIP Homotypic Interaction Motifs of RIPK3 in RIPK1-Dependent Cell Death and Lymphoproliferative Disease

Haiwei Zhang; Xiaoxia Wu; Xiaoming Li; Ming Li; Fang Li; Lingxia Wang; Xixi Zhang; Yue Zhang; Yan Luo; Hui Wang; Yiguo Jiang; Haibing Zhang

doi:10.1016/j.celrep.2020.107650

Crucial Roles of the RIP Homotypic Interaction Motifs of RIPK3 in RIPK1-Dependent Cell Death and Lymphoproliferative Disease

Cell Rep. 2020 May 19;31(7):107650. doi: 10.1016/j.celrep.2020.107650.

Authors

Haiwei Zhang¹, Xiaoxia Wu¹, Xiaoming Li¹, Ming Li¹, Fang Li¹, Lingxia Wang¹, Xixi Zhang¹, Yue Zhang², Yan Luo², Hui Wang³, Yiguo Jiang⁴, Haibing Zhang⁵

Affiliations

¹ CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
² Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Institute for Chemical Carcinogenesis, State Key Laboratory of Respiratory Disease, Guangzhou Medical University, Guangzhou, China.
⁵ CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. Electronic address: hbzhang@sibs.ac.cn.

PMID: 32433959
DOI: 10.1016/j.celrep.2020.107650

Abstract

Receptor-interacting protein kinase 3 (RIPK3) has been identified as an essential regulator of necroptosis, apoptosis, and inflammatory signaling. RIPK3 contains an N-terminal kinase domain and a C-terminal RIP homotypic interaction motif (RHIM). However, the physiological roles of RIPK3 RHIM remain unclear. Here we generate knockin mice endogenously expressing the RIPK3 RHIM mutant, RIPK3^V448P. Cells expressing RIPK3^V448P are resistant to RIPK1 kinase-dependent apoptosis and necroptosis, and Ripk3^V448P/V448P mice rescue embryonic lethality of Fadd-deficient mice by intercrossing. Strikingly, Ripk3^V448P/V448PFadd^-/- mice display more severe lymphoproliferative disease with a marked increase in abnormal CD3⁺B220⁺ lymphocytes compared with Ripk3^-/-Fadd^-/- mice. More importantly, these inflammatory morbidities in Ripk3^V448P/V448PFadd^-/- mice are profoundly inhibited by additional deletion of Ripk1. Taken together, these results reveal a previously unidentified physiological function of RHIM of RIPK3 in regulating RIPK1-dependent cell death and lymphoproliferative disease.

Keywords: FADD; MLKL; RHIM; RIPK1; RIPK3; Receptor-interacting protein homotypic interaction motifs; embryonic development; inflammation; lymphoproliferative disease; necroptosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Death / genetics*
Lymphoproliferative Disorders / genetics*
Mice
Receptor-Interacting Protein Serine-Threonine Kinases / metabolism*

Substances

Receptor-Interacting Protein Serine-Threonine Kinases
Ripk1 protein, mouse
Ripk3 protein, mouse