Humanin enhances the cellular response to stress by activation of chaperone-mediated autophagy

Increased oxidative stress and loss of proteostasis are characteristics of aging. Failure to remove the oxidative stress-damaged components has been recognized to play critical roles in the pathophysiology of common age-related disorders including neurodegenerative disease such as Parkinson’s disease and Alzheimer’s disease, and cardiovascular diseases such as myocardial infarction and heart failure. Strategies to diminish oxidative stress or effectively eliminate oxidative-damaged intracellular proteins may therefore provide novel therapeutic option for many age-related diseases. Chaperone-mediated autophagy (CMA) allows for selective degradation of soluble proteins in lysosomes, contributing to the cellular quality control and maintenance of cellular energetic balance [1]. CMA substrate proteins are targeted by the chaperone hsc70 to the lysosomal surface where, upon binding to the lysosome-associated membrane protein type 2A (LAMP2A), they are translocated into the lysosomal lumen for degradation. CMA is activated by oxidative stress to facilitate degradation of damaged proteins [2], thereby eliminating the insults of oxidative stress. Given the fact that CMA activity declines with age [3], and oxidative damage in cells increases during aging, CMA activators hold the potential for development as a new generation of treatment option for age-related diseases. In our recent study, we identified that humanin (HN), an antiapoptotic, mitochondria-associated peptide is an endogenous CMA activator [4]. We demonstrated that HN protects multiple cell types including cardiomyoblasts, primary cardiomyocytes and dopaminergic neuronal cells from oxidative stress-induced cell death in a CMAdependent manner. In fact, this protective effect is lost in CMA-incompetent cells (LAMP-2A knockdown). Both exogenously added HN as well as the endogenously generated HN cooperate in CMA activation. Thus, knockdown of endogenous HN decreases CMA activation in response to oxidative stress. Both endogenous and exogenous HN localize at the lysosomal membrane where they cooperate to enhance CMA efficiency. HN acts by stabilizing binding of the chaperone HSP90 to the upcoming substrates at the cytosolic side of lysosomal membrane. Our study provided the first evidence that regulatory Editorial: Autophagy and Cell Death