LRRK2 suppresses lysosome degradative activity in macrophages and microglia through MiT-TFE transcription factor inhibition

Abstract Cells maintain optimal levels of lysosome degradative activity to protect against pathogens, clear waste and generate nutrients. Here we show that LRRK2, a protein that is tightly linked to Parkinson’s disease, negatively regulates lysosome degradative activity in macrophages and microglia via a transcriptional mechanism. Depletion of LRRK2 and inhibition of LRRK2 kinase activity enhanced lysosomal proteolytic activity and increased the expression of multiple lysosomal hydrolases. Conversely, the kinase hyperactive LRRK2 G2019S Parkinson’s disease mutant suppressed lysosomal degradative activity and gene expression. We identified MiT-TFE transcription factors (TFE3, TFEB and MITF) as mediators of LRRK2-dependent control of lysosomal gene expression. LRRK2 negatively regulated the abundance and nuclear localization of these transcription factors and their depletion prevented LRRK2-dependent changes in lysosome protein levels. These discoveries define a role for LRRK2 in controlling lysosome degradative activity and support a model wherein LRRK2 hyperactivity may increase Parkinson’s disease risk by suppressing lysosome degradative activity. Significance Statement This study defines a homeostatic mechanism that allows macrophages and microglia to match the degradative activity of their lysosomes to ongoing changes in cellular demand. It shows that the leucine rich repeat kinase 2 (LRRK2) protein suppresses lysosome degradative activity by inhibiting the expression and nuclear localization of the MiT-TFE family of transcription factors that control the expression of multiple genes that encode lysosome proteins. It further demonstrates that a Parkinson’s disease mutation that hyperactivates LRRK2 kinase activity limits the degradative activity of lysosomes more strongly. These findings support a model wherein LRRK2 protects cells from excessive lysosome degradative activity and suggest that overactivation of this pathway may increase Parkinson’s disease risk by limiting the degradative activity of lysosomes.