Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan.
Program of Basic Biology, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Hiroshima, Japan.
Nat Commun. 2024 Oct 10;15(1):8777. doi: 10.1038/s41467-024-53097-5.
VAMP-associated protein (VAP) is a type IV 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 is transported to 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.
VAMP 相关蛋白（VAP）是内质网（ER）的一种 IV 型整合跨膜蛋白。人类 VAPB/ALS8 的突变与肌萎缩侧索硬化症（ALS）有关。VAPB（果蝇 Vap33）的 N 端主要精子蛋白（MSP）结构域被切割、分泌，并作为几种细胞表面受体的信号配体发挥作用。尽管 VAPB 的细胞外功能开始被理解，但尚不清楚面向细胞质的 VAPB/Vap33 MSP 结构域如何分泌到细胞外空间。在这里，我们表明 Vap33 被运输到质膜，其中 MSP 结构域通过拓扑倒置暴露在细胞外。基质金属蛋白酶 1/2（Mmp1/2）切割外化的 MSP 结构域。过表达 Mmp1 可恢复源自与 ALS8 相关的 Vap33 突变体的细胞外 MSP 结构域减少的水平。我们提出了一种前所未有的 ER 驻留膜蛋白分泌机制，这可能有助于 ALS8 的发病机制。
