IASPP is a novel autophagy inhibitor in keratinocytes

Abstract

IASPP is an evolutionarily conserved p53 inhibitor whose expression is often upregulated in human cancers. We have recently shown that iASPP is a crucial regulator of epidermal homeostasis. Here we report that iASPP also acts as autophagy inhibitor in keratinocytes. Our data show that iASPP depletion protects keratinocytes from apoptosis by modulating NOXA expression. In our model, iASPP expression can affect mitochondrial fission-fusion cycle, mass, and shape. iASPP silenced keratinocytes show an overall disorganization of cytosolic compartments and increased metabolic stress via deregulation of mTORC1 signaling. Moreover, increased lipidated LC3 protein confirmed autophagy activation in iASPP-depleted cells. We have identified a novel mechanism modulating autophagy in keratinocytes which relies upon iASPP expression specifically reducing Atg5/Atg12 interaction with Atg16L1, essential for autophagosome formation or maturation. In organotypic culture we further explored the link between autophagy and differentiation and showed how autophagy impairment affects epidermal terminal differentiation. Our data provide an alternative mechanism to explain how epithelial integrity is maintained against environmental stressors and may also improve understanding of the etiology of skin diseases characterized by defects in differentiation and DNA damage responses.