Therefore, we have explored how CMA activating compounds may restore CMA activity in aged T cells boosting T cell function. Dynamic organization of the receptor for chaperone-mediated autophagy at the lysosomal membrane. Interestingly, genetic restoration of LAMP-2A expression in aged cells enhances T cell responses. Furthermore, our data supports that LAMP-2A expression and CMA activity are down-regulated in aged T cells, which correlates with the age-associated decreases in T cell function. We have used these novel CMA activators to identify target genes involved in the regulation of CMA in T cells. We have found that retinoic acid receptor alpha (RARĪ±) signaling inhibits CMA, and that modulation of RARĪ± signaling with chemically modified retinoic acid derivatives leads to CMA activation. However, the signaling pathways that regulate CMA activity during the immune response and cell type-specific functions of CMA are not fully characterized. We have previously reported that CMA is upregulated in activated CD4+ T cells, where it is required to support proliferation and cytokine production. Lysosomes are an important site for the degradation of misfolded proteins, which are trafficked to this organelle by the pathways of macroautophagy, chaperone-mediated autophagy and endocytosis. The receptor multimerizes and the substrate translocates into the lysosome to be degraded. One essential element of proteostasis is the disposal of misfolded proteins by the cellular pathways of protein degradation. In CMA, the chaperone Hsc70 recognizes and binds a CMA-targeting motif in the substrate and brings it to the LAMP-2A receptor on the lysosomal membrane. Chaperone mediated autophagy (CMA) is a selective form of autophagy that targets soluble cytoplasmic proteins for degradation. Autophagy is a cellular quality control mechanism that degrades and recycles cellular components in the lysosome to maintain cellular homeostasis and to regulates protein levels in response to stimuli.
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