内质网
细胞生物学
分泌物
细胞外
分泌途径
跨膜蛋白
分泌蛋白
生物
胞浆
ER保留
跨膜结构域
高尔基体
受体
突变体
生物化学
基因
酶
作者
Takahiro Chihara,Kosuke Kamemura,Rio Kozono,Misako Okumura,Daisuke Koga,Satoshi Kusumi,Sayaka Sekine,Daichi Kamiyama
出处
期刊:Research Square - Research Square
日期:2023-04-14
标识
DOI:10.21203/rs.3.rs-2757221/v1
摘要
Abstract VAMP-associated protein (VAP) is a type II integral transmembrane protein at the endoplasmic reticulum (ER). Mutations in human VAPB/ALS8 are associated with amyotrophic lateral sclerosis (ALS). The N-terminal major sperm protein (MSP) domain of VAPB (Drosophila Vap33) is cleaved, secreted, and acts as a signaling ligand for several cell-surface receptors. Although extracellular functions of VAPB are beginning to be understood, it is unknown how the VAPB/Vap33 MSP domain facing the cytosol is secreted to the extracellular space. Here we show that Vap33 uses the ER-Golgi conventional secretion pathway to reach the plasma membrane, where the MSP domain is exposed extracellularly by topological inversion. The externalized MSP domain is cleaved by Matrix metalloproteinase 1/2 (Mmp1/2). Overexpression of Mmp1 restores decreased levels of extracellular MSP domain derived from ALS8-associated Vap33 mutants. We propose an unprecedented secretion mechanism for an ER-resident membrane protein, which may contribute to ALS8 pathogenesis.
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