Transient receptor potential vanilloid 1 activation induces autophagy in thymocytes through ROS-regulated AMPK and Atg4C pathways
Open Access
- 29 June 2012
- journal article
- research article
- Published by Oxford University Press (OUP) in Journal of Leukocyte Biology
- Vol. 92 (3), 421-431
- https://doi.org/10.1189/jlb.0312123
Abstract
Autophagy is a highly conserved process involved in lymphocyte development and differentiation. Herein, we demonstrated for the first time that triggering of TRPV1 by the specific agonist CPS induces autophagy in mouse thymocytes. TRPV1-dependent autophagy required [Ca2+]i and ROS generation, resulting in AMPK activation. CPS specifically increased 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 a prosurvival process, as its inhibition triggered apoptosis of thymocytes: this effect was accompanied by down-regulation of Atg4C, Bcl-XL, and 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 DPdull. Interestingly, we found that CPS induces autophagy of DPdull cells, and inhibition of CPS-induced autophagy by the 3-MA autophagic inhibitor induces apoptosis of DPdull cells, suggesting the presence of an interplay between autophagic survival and apoptotic cell death. Overall, our findings suggest that DPdull cells constitute a distinct thymocyte subpopulation involved in the homeostatic control of cellularity and in the responses to chemical stress signals during thymocyte maturation, via regulating autophagy and apoptosis in a TRPV1-dependent manner.Keywords
Funding Information
- Italian Ministry of Education, Universities and Research (PRIN 2007-2009)
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