Thyroid hormone upregulates LAMP2 expression and lysosome activity

Abstract

Thyroid hormone (T₃)-induced autophagy and its biological significance have been extensively investigated in recent years. However, limited studies to date have focused on the important role of lysosomes in autophagy. In this study, we explored the effects of T₃ on lysosomal protein expression and trafficking in detail. Our findings showed that T₃ activates rapid lysosomal turnover and expression of numerous lysosomal genes, including TFEB, LAMP2, ARSB, GBA, PSAP, ATP6V0B, ATP6V0D1, ATP6V1E1, CTSB, CTSH, CTSL, and CTSS, in a thyroid hormone receptor-dependent manner. In a murine model, LAMP2 protein was specifically induced in mice with hyperthyroidism. T₃-promoted microtubule assembly was significantly disrupted by vinblastine, resulting in accumulation of the lipid droplet marker PLIN2. In the presence of the lysosomal autophagy inhibitors bafilomycin A1, chloroquine and ammonium chloride, we observed substantial accumulation of LAMP2 but not LAMP1 protein. T₃ further enhanced the protein levels of ectopically expressed LAMP1 and LAMP2. Upon knockdown of LAMP2, cavities of lysosomes and lipid droplets accumulated in the presence of T₃, although the changes in LAMP1 and PLIN2 expression were less pronounced. More specifically, the protective effect of T₃ against ER stress-induced death was abolished by knockdown of LAMP2. Our collective results indicate that T₃ not only promotes lysosomal gene expression but also LAMP protein stability and microtubule assembly, leading to enhancement of lysosomal activity in digesting any additional autophagosomal burden.

Keywords: ER stress; LAMP2; Lysosome; Thyroid hormone; Vesicle trafficking.