Capn3b-deficient zebrafish model reveals a key role of autoimmune response in LGMDR1  

作　　者：Yayue Chen Delai Huang Aixuan Xie Ying Shan Shuyi Zhao Ce Gao Jun Chen Hui Shi Weihuan Fang Jinrong Peng 

机构地区：[1]MOE Key Laboratory for Molecular Animal Nutrition,College of Animal Sciences,Zhejiang University,Hangzhou,Zhejiang 310058,China [2]College of Life Sciences,Zhejiang University,Hangzhou,Zhejiang 310058,China

出　　处：《Journal of Genetics and Genomics》2024年第12期1375-1388,共14页遗传学报（英文版）

基　　金：financially supported by National Natural Science Foundation of China(U21A20198 and 32100658);the National Key R&D Program of China(2018YFA0800502)。

摘　　要：Mutations in calcium-dependent papain-like protease CALPAIN3(CAPN3)cause Limb-Girdle Muscular Dystrophy Recessive Type 1(LGMDR1),the most common limb-girdle muscular dystrophy in humans.In addition to progressive muscle weakness,persistent inflammatory infiltration is also a feature of LGMDR1.Despite the underlying mechanism remaining poorly understood,we consider that it may relate to the newly defined role of CAPN3/Capn3b in the nucleolus.Here,we report that the loss of function of zebrafish capn3b,the counterpart of human CAPN3,induces an autoimmune response akin to that in LGMDR1 patients.capn3b mutant larvae are more susceptible to Listeria monocytogenes injection,characterized by recruiting more macrophages.Under germ-free conditions,transcriptome analysis of the capn3b mutant muscle reveals a significant upregulation of the chemokine-production-related genes.Coincidently,more neutrophils are recruited to the injury site imposed by either muscle stabbing or tail fin amputation.Nucleolar proteomic analysis and enzymatic assays reveal NKAP,an activating factor of the NF-k B pathway,to be a target of CAPN3.We conclude that the accumulation of Nkap and other factors in the capn3b mutant may be involved in the over-activation of innate immunity.Our studies indicate that the zebrafish capn3b mutant is a powerful model for studying the immunity-related progression of human LGMDR1.

关 键 词：capn3b AUTOIMMUNITY LGMDR1 NEUTROPHIL Nkap ZEBRAFISH 

分 类 号：R746.2[医药卫生—神经病学与精神病学] R-332[医药卫生—临床医学]