Fig. 6: Schematic representation of CatB and its substrates in autophagy.
From: Cathepsin B in programmed cell death machinery: mechanisms of execution and regulatory pathways
Loss of growth factor stimulation or nutritional inputs like glucose leads to the activation of the ULK complex and subsequently drives phagophore assembly. The phagophore elongates and circularizes to form the autophagosome, which then docks with lysosomes. Under homeostatic conditions, CatB directly cleaves the lysosomal calcium channel MCOLN1 and negatively regulates the efflux of calcium and activation of the PPP3. Inhibition of PPP3 prevents its ability to dephosphorylate and activate TFEB. Dephosphorylated TFEB initiates autophagy. Therefore, CatB works as an apical signal controlling lysosomal dynamics and autophagy. ANTXR2-mediated delivery of LF requires autophagy flux, which is triggered by lysosome fusion and CatB. Obesity-induced lipotoxicity and ER stress, or stressed lysosomal mediated autophagosome accumulation involves CatB activity reduction or lysosomal leakage. AMPK AMP-activated protein kinase, ANTXR2 anthrax toxin receptor 2, CatB cathepsin B, ER endoplasmic reticulum, LF lethal factor, MCOLN1 mucolipin TRP cation channel 1, PPP3 Protein Phosphatase 3, TFEB transcription factor EB, ULK Unc-51 like autophagy activating kinase.
