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Title: Transient Receptor Potential Vanilloid 1 (TRPV1) activation induces autophagy in thymocytes through ROS-regulated AMPK and Atg4C pathways.
Authors: Farfariello, Valerio
Tutor: Santoni, Giorgio
Keywords: Autophagy
Issue Date: 28-Mar-2012
Abstract: Autophagy is a highly conserved process involved in lymphocyte development and differentiation. Herein, we demonstrated for the first time that triggering of Transient Receptor Potential Vanilloid 1 (TRPV1) by the specific agonist capsaicin (CPS) induces autophagy in mouse thymocytes. TRPV1-dependent autophagy required calcium influx and ROS generation resulting in AMP-activated kinase (AMPK) activation. CPS specifically increased autophagy related 4C (Atg4C) mRNA expression and induced oxidation of Atg4C protein by ROS generation. TRPV1-triggered autophagy was Atg6/Beclin-1-dependent, as demonstrated by the use of Beclin-1+/- transgenic mice, and involved ROS- and AMPK-mediated up-regulation of Beclin-1 expression. Autophagy is activated as pro-survival process since its inhibition triggered apoptosis of thymocytes: this effect was accompanied by down-regulation of Atg4C, Bcl-XL and immunity-related GTPase family M (Irgm1) mRNA expression, decreased Bcl-XL and Beclin-1 protein levels and caspase-3 activation, suggesting the existence of a molecular interplay between autophagic and apoptotic programs. TRPV1 activation by CPS altered the expression of CD4 and CD8α antigens, inducing the development of a double positive subpopulation expressing lower levels of both receptors (DPdull), representing an intermediate stage of thymocyte maturation. Interestingly, we found that DPdull represent the thymocyte subpopulation undergoing autophagy upon CPS treatment and that, when autophagy is inhibited, it becomes apoptotic. Our findings suggest that DPdull cells are able to respond either to survival or death signals and that TRPV1 channel dependent autophagy/apoptosis could play a major role in thymocyte development.

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