Abstract
Autophagy and the ubiquitin-proteasome system (UPS) control thymus cell homeostasis under resting and endoplasmic reticulum (ER) stress conditions. Several evidence support a cross-talk between UPS and autophagy; abrogation of UPS responses stimulates autophagy, and vice versa the inhibition of autophagy alters the UPS functions.Herein, we found that TRPV1 activation induces ER stress, proteasome dysfunction and autophagy in thymocytes by modulating the expression of UPR-related genes. The TRPV1-mediated autophagy prevents the UPR activation by inhibiting BiP, Grp94 and ERp57 chaperone protein expression.Thymocytes from TRPV1 KO mice display both autophagy and proteasome dysfunctions, resulting in increased apoptotic cells and reduced total DP thymocyte number.In addition, positive selection of thymocytes triggered by anti-TCRβ/CD2 Ab-mediated costimulation induces apoptosis in thymocytes from TRPV1 KO as compared with WT mice. Stimulation of TRPV1 KO thymocytes with anti-TCRβ/CD2 mAbs modulates the expression of CD4 antigen on purified DP thymocytes, with reduced number of mature, single positive (SP) CD4 and increased number of immature SP CD4low and DP CD4lowCD8+ thymocytes, further supporting the intrinsic role of TRPV1 in T cell maturation. Finally, a reduction in CD8+ and CD4+ T cells is evidenced in the peripheral blood and spleen of TRPV1 KO, as compared with WT mice. Therapeutic strategy by restraining or stimulating the TRPV1 expression and functions in thymocytes might represent a new pharmacological tool in the regulation of different inflammatory T cell responses.
Highlights
Autophagy and the ubiquitin-proteasome system (UPS) constitute the major intracellular degradation pathways controlling cellular homeostasis under normal conditions and cellular stress [1]
The apoptotic regulator Atf4 transcription factor (Figure 5F) and ERp57 (Figure 5G) protein levels were up regulated whereas BiP (Figure 5H) and Grp94 (Figure 5I) unfolded protein response (UPR) proteins were reduced in TRPV1 KO compared with WT thymocytes. These findings demonstrate that the expression of TRPV1 in thymocytes www.impactjournals.com/oncotarget is crucial in regulating autophagy, apoptosis and UPR activity
Several evidence support the existence of a crosstalk between UPS and autophagy [9, 28]
Summary
Autophagy and the ubiquitin-proteasome system (UPS) constitute the major intracellular degradation pathways controlling cellular homeostasis under normal conditions and cellular stress [1]. Autophagy is a cellular adaptive response to stress conditions, such as nutrient, growth factor deprivation or oxidative stress. This process is mainly involved in the degradation of longlived proteins and excess/damaged organelles [2]. Mild to moderate ER stress induces autophagy as a compensatory cell survival mechanism by relieving proteasome inhibitor-induced ER stress, whereas severe or chronically prolonged ER stress deteriorates cellular functions with a switch from an adaption program to apoptotic cell death [7, 8]. Several evidence support the existence of an interplay between the UPS and autophagy [9]: inhibition of UPS often induces autophagy whilst inhibition of autophagy alters the UPS function [1]
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