SMCR8 negatively regulates AKT and MTORC1 signaling to modulate lysosome biogenesis and
modulate
tissue homeostasis
期刊名称： Autophagy
作者： Lan, Yungang,Sullivan, Peter M.,Hu, Fenghua
年份： 2019年
关键词： AKT-MTORC1;ALS/FTLD;autophagy;C9orf72-SMCR8-
WDR41;inflammation;lysosome
摘要：The intronic hexanucleotide expansion in the C9orf72 gene is one of the leading causes of frontotem- poral lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), two devastating neurodegen- erative diseases. C9orf72 forms a heterodimer with SMCR8 (Smith-Magenis syndrome chromosome region, candidate 8) protein. However, the physiological function of SMCR8 remains to b
e characterized. Here we report that ablation of SMCR8 in mice results in splenomegaly with autoimmune phenotypes similar to that of C9orf72 deficiency. Furthermore, SMCR8 loss leads to a drastic decrease of C9orf72 protein levels. Many proteins involved in the macroautophagy-lysosome pathways are downregulated upon SMCR8 loss due to elevated activation of MTORC1 and AKT, which also leads to increased spine density in the Smcr8 knockout neurons. In summary,
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