Regulation of lysosomal dynamics and autophagy by CTSB/cathepsin B

Cysteine cathepsins are responsible for driving proteolytic degradation within the lysosome and in the extralysosomal milieu. They also have an integral role in autophagy, antigen presentation, cellular stress signaling, metabolism and lysosome-dependent cell death. Here, we discuss our findings on the role of CTSB (cathepsin B), a member of the cysteine cathepsin family, in regulating the bioavailability of lysosomes and autophagosomes and consider how this regulatory response influences host susceptibility to infectious agents. Our study demonstrates that under homeostatic conditions CTSB cleaves the calcium channel MCOLN1/TRPML1 in the lysosomes, maintaining suppression of the transcription factor TFEB and reducing expression of lysosomal and autophagy-related proteins. This response controls the number of lysosomes and autophagosomes in the cell. However, the activity of CTSB is exploited by the cytosolic bacterium Francisella novicida, leading to enhanced survival of the pathogen and increased susceptibility of the host to infection.