Abstract
Lysosomes are the main proteolytic compartments of mammalian cells comprising of a battery of hydrolases. Lysosomes dispose and recycle extracellular or intracellular macromolecules by fusing with endosomes or autophagosomes through specific waste clearance processes such as chaperone-mediated autophagy or microautophagy. The proteolytic end product is transported out of lysosomes via transporters or vesicular membrane trafficking. Recent studies have demonstrated lysosomes as a signaling node which sense, adapt and respond to changes in substrate metabolism to maintain cellular function. Lysosomal dysfunction not only influence pathways mediating membrane trafficking that culminate in the lysosome but also govern metabolic and signaling processes regulating protein sorting and targeting. In this review, we describe the current knowledge of lysosome in influencing sorting and nutrient signaling. We further present a mechanistic overview of intra-lysosomal processes, along with extra-lysosomal processes, governing lysosomal fusion and fission, exocytosis, positioning and membrane contact site formation. This review compiles existing knowledge in the field of lysosomal biology by describing various lysosomal events necessary to maintain cellular homeostasis facilitating development of therapies maintaining lysosomal function.
Highlights
Seminal studies by Duve Laboratory uncovered lysosome as the cellular compartment for the degradation of biological macromolecules [1,2]
Trans-SNARE complex brings the lysosome in a close proximity to the plasma membrane (PM) to initiate the fusion of lysosome and PM. (5) The fusion of lysosome and PM triggers an efflux of lysosomal enzyme aSMase, which is retain on the PM to convert sphingomyelin into ceramide, (6) leading to an inward configuration of the PM to facilitate endocytosis-dependent removal and restoration of damaged PM
Given that the proteins undergoing degradation through chaperone-mediated autophagy (CMA) exhibit diverse roles in a myriad of intracellular processes, it is plausible that changes in lysosome-associated membrane protein-2A (LAMP-2A) function and lysosomal biogenesis could have a significant impact on degradation of CMA-targeted proteins and lead to significant impacts on cellular metabolism and function
Summary
Seminal studies by Duve Laboratory uncovered lysosome as the cellular compartment for the degradation of biological macromolecules [1,2]. Acid hydrolases and lysosomal membrane proteins (LMPs) dictate lysosomal function [9,10]. LMPs are pivotal in maintaining lysosomal membrane integrity, luminal acidification, an ionic gradient and homeostasis, protein translocation and membrane trafficking [9,10]. Beyond the lysosome’s canonical role in cellular waste disposal, it is implicated in nutrient sensing, immune cell signaling, metabolism, and membrane repair [12]. Emerging studies show that intra-lysosomal and extra-lysosomal processes govern lysosomal fusion and fission [13], exocytosis [14], positioning [15] and formation of a membrane contact site [16]. Lysosomes form a membrane contact site with other organelles to exchange signaling information, shuttle metabolites and render ionic homeostasis [16,17]. This review compiles existing knowledge in the field of lysosomal physiology and function by describing lysosomal events necessary in maintaining lysosome function and cellular homeostasis
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