Defect Of Autophagy Activates YAP By P62-mediated Translocation Of AMOT

Autophagy,a major catabolic system in eukaryotic cells,is important for the maintenance of cell homeostasis.By forming the double-membraned autophagosomes in the cytoplasm,autophagy mediates the degradation of damaged organelles and misfolded proteins in the lysosomes.Autophagy deficiency has been reported to be related to a variety of human diseases including aging,metabolic syndrome,neurodegeneration,and especially cancer.p62,as a selective autophagy adaptor,forms protein aggregates depending on its UBA domain binding ubiquitin protein and PB1 domain selfoligomerization.Meanwhile,p62 binds directly to LC3 through its LC3 interaction region(LIR)to shuttle substrates to autophagosomes for degradation.Liver-specific Atg5-/-or Atg7-/-mice develop liver adenomas.The size of the Atg7-/-liver tumor is reduced by simultaneous deletion of p62.These results suggest that autophagy is important for the suppression of spontaneous tumorigenesis and p62 accumulation contributes to tumor progression.However,the molecular mechanism in this event is still poorly understood.The Hippo signaling pathway is involved in the transmission of signals through a series of related kinase interactions and cascades of phosphorylation to inhibit the activity of the transcriptional coactivator YAP,and controlling cell proliferation and organ size.Persistent activation of YAP protein can induce tumorgenesis.When Hippo signaling pathway is activated,large tumor suppressor kinanse(LATS)can phosphorylate YAP and then promote YAP cytoplasmic retention and proteasome degradation.Meanwhile,AMOT family proteins,originally identified as angiostatin binding proteins and implicated in the regulation of endothelial cell migration,can also be phosphorylated by kinanse LATS,negatively regulating YAP activity,and hence,inhibition of cell growth and proliferation are achieved.In this study,we found that p62 accumulated in autophagy deficient cells and formed p62 bodies,which can hijack AMOT family proteins,weakening interaction between AMOT family proteins and YAP.This leads YAP to stay in nucles and activated even when cells are under dense condition.When knocking out p62 in autophagy deficient cells,the interation between AMOT family proteins and YAP was enhanced and YAP relocated to cytoplasm,suggesting YAP activity was inhibited.Our findings indicate that the process associated with p62 accumulation results in hyperactivation of YAP and delineates unexpected roles of autophagy in controlling the cell proliferation and survival,which could explain why autophagy defect can induce tumorgenesis.