Deamidation enables pathogenic SMAD6 variants to activate the BMP signaling pathway  

作　　者：Ling Li Lei Lu Ziqi Xiao Jingyi Lv Hefeng Huang Bo Wu Tongjin Zhao Chengtao Li Weimin Wang Hongyan Wang 

机构地区：[1]Obstetrics and Gynecology Hospital,State Key Laboratory of Genetic Engineering,Institute of Reproduction and Development,and Children’s Hospital,Fudan University,Shanghai 200090,China [2]Shanghai Key Laboratory of Metabolic Remodeling and Health,Institute of Metabolism and Integrative Biology,Fudan University,Shanghai 200438,China [3]Prenatal Diagnosis Center of Shenzhen Maternity&Child Healthcare Hospital,Shenzhen 518028,China [4]Shanghai Medical College,Fudan University,Shanghai 200032,China [5]Department of Pharmacy,College of Life Sciences,China Jiliang University,Hangzhou 310018,China

出　　处：《Science China(Life Sciences)》2024年第9期1915-1927,共13页中国科学（生命科学英文版）

基　　金：supported by the National Key Research and Development Program of China(2021YFC2701101);the National Natural Science Foundation of China(82150008,81930036);Commission for Science and Technology of Shanghai Municipality(20JC1418500);Open Fund Project of Guangdong Academy of Medical Sciences(YKY-KF202202)。

摘　　要：The BMP signaling pathway plays a crucial role in regulating early embryonic development and tissue homeostasis.SMAD6 encodes a negative regulator of BMP,and rare variants of SMAD6 are recurrently found in individuals with birth defects.However,we observed that a subset of rare pathogenic variants of SMAD6 consistently exhibited positive regulatory effects instead of the initial negative effects on the BMP signaling pathway.We sought to determine whether these SMAD6 variants have common pathogenic mechanisms.Here,we showed that pathogenic SMAD6 variants accompanying this functional reversal exhibit similar increases in deamidation.Mechanistically,increased deamidation of SMAD6 variants promotes the accumulation of the BMP receptor BMPR1A and the formation of new complexes,both of which lead to BMP signaling pathway activation.Specifically,two residues,N262 and N404,in SMAD6 were identified as the crucial sites of deamidation,which was catalyzed primarily by glutamine-fructose-6-phosphate transaminase 2(GFPT2).Additionally,treatment of cells harboring SMAD6 variants with a deamidase inhibitor restored the inhibitory effect of SMAD6 on the BMP signaling pathway.Conversely,when wild-type SMAD6 was manually simulated to mimic the deamidated state,the reversed function of activating BMP signaling was reproduced.Taken together,these findings show that deamidation of SMAD6 plays a crucial role in the functional reversal of BMP signaling activity,which can be induced by a subset of various SMAD6 variants.Our study reveals a common pathogenic mechanism shared by these variants and provides a potential strategy for preventing birth defects through deamidation regulation,which might prevent the off-target effects of gene editing.

关 键 词：SMAD6 DEAMIDATION BMP signaling pathway GFPT2 

分 类 号：R714[医药卫生—妇产科学]