LAMP2A

Lysosome-associated membrane glycoprotein 2A (LAMP2A) is a transmembrane protein of the lysosomal membrane that serves as the receptor for chaperone-mediated autophagy (CMA). LAMP2A is one of three splice isoforms of the LAMP2 gene (LAMP2A, LAMP2B, LAMP2C) produced by alternative splicing; LAMP2A is the isoform that mediates CMA, whereas the others are associated with different aspects of lysosome biology.

In CMA, cytosolic chaperones such as HSC70 recognize substrates containing a KFERQ-like motif and deliver them to the lysosome. The substrate–HSC70 complex binds to LAMP2A on the lysosomal membrane, and binding promotes the assembly of LAMP2A into a multimeric translocation complex. The substrate is then unfolded and translocated into the lysosome for degradation by resident proteases. LAMP2A levels at the lysosomal membrane are rate-limiting for CMA, and turnover and recycling of LAMP2A regulate CMA activity. Age-related declines in CMA are linked to reduced LAMP2A stability and abundance at lysosomes, contributing to the accumulation of damaged proteins. Manipulating LAMP2A expression or CMA activity has shown protective effects in cellular and animal models of aging and neurodegenerative disease.

Clinically, LAMP2 deficiency causes Danon disease, an X-linked lysosomal storage disorder characterized by cardiomyopathy, myopathy, and variable cognitive impairment. Beyond this genetic disorder, CMA and LAMP2A are studied for their roles in aging, cancer, and neurodegeneration, with growing evidence that maintaining CMA through LAMP2A regulation can influence cellular proteostasis.