Abstract
Communication between organelles is essential for their cellular homeostasis. Neurodegeneration reflects the declining ability of neurons to maintain cellular homeostasis over a lifetime, where the endolysosomal pathway plays a prominent role by regulating protein and lipid sorting and degradation. Here we report that TMEM16K, an endoplasmic reticulum lipid scramblase causative for spinocerebellar ataxia (SCAR10), is an interorganelle regulator of the endolysosomal pathway. We identify endosomal transport as a major functional cluster of TMEM16K in proximity biotinylation proteomics analyses. TMEM16K forms contact sites with endosomes, reconstituting split-GFP with the small GTPase RAB7. Our study further implicates TMEM16K lipid scrambling activity in endosomal sorting at these sites. Loss of TMEM16K function led to impaired endosomal retrograde transport and neuromuscular function, one of the symptoms of SCAR10. Thus, TMEM16K-containing ER-endosome contact sites represent clinically relevant platforms for regulating endosomal sorting.
Highlights
Communication between organelles is essential for their cellular homeostasis
Using bungarotoxin staining as a marker for neuromuscular junctions (NMJ), we found a progressive reduction in the size of the NMJ (Fig. 1b, c)
These animals lacking neuronal TMEM16K displayed increased hindlimb clasping, as well as an impaired ability to complete a ledge-walking test (Fig. 1e). These results demonstrate a phenotypic linkage between loss of TMEM16K and impaired neuromuscular function that is conserved between mice and human
Summary
Communication between organelles is essential for their cellular homeostasis. Neurodegeneration reflects the declining ability of neurons to maintain cellular homeostasis over a lifetime, where the endolysosomal pathway plays a prominent role by regulating protein and lipid sorting and degradation. The single TMEM16 family member in yeast, Ist2p, was one of the first reported MCS tethers shown to play a vital role in lipid homeostasis at contact sites between the endoplasmic reticulum (ER) and plasma membrane[30,31,32]. Outside of the yeast studies, TMEM16 family members have been extensively investigated far for roles other than those at membrane contact sites To evaluate their potential role in interorganelle communication we focus on the lipid scramblase TMEM16K33, the least divergent member of the mammalian family[25] (Supplementary Fig. 1a) responsible for an autosomal recessive form of progressive neurodegenerative disease, spinocerebellar ataxia (SCAR10)[34,35,36]
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