LRRK2 Suppresses Lysosome Degradative Activity in Macrophages and Microglia Through MiT-TFE Transcription Factor Inhibition

Yadavalli, Narayana; Ferguson, Shawn M.

doi:10.1101/2022.12.17.520834

Cited by 12 publications

(18 citation statements)

References 96 publications

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“…At the lysosome LRRK2 is activated and found to phosphorylate Rab proteins thereby recruiting JIP4, which promotes formation of tubular structures that release membranous content from lysosomes ( 12 ). Recent work reveals that LRRK2 negatively regulates lysosomal degradative activity in macrophages and microglia via a transcriptional mechanism involving transcription factor E3 (TFE3) ( 32 ). Depletion of LRRK2 and inhibition of LRRK2 kinase activity both enhance lysosomal proteolytic activity and increase the expression of multiple lysosomal hydrolases ( 32 ).…”

Section: Introductionmentioning

confidence: 99%

“…Recent work reveals that LRRK2 negatively regulates lysosomal degradative activity in macrophages and microglia via a transcriptional mechanism involving transcription factor E3 (TFE3) ( 32 ). Depletion of LRRK2 and inhibition of LRRK2 kinase activity both enhance lysosomal proteolytic activity and increase the expression of multiple lysosomal hydrolases ( 32 ). Other work has revealed that LRRK2 kinase activity controls PD relevant lipids such as bis(monoacylglycerol)phosphates as well as glycosphingolipids at the lysosome ( 33, 34 ).…”

Section: Introductionmentioning

confidence: 99%

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Parkinson’s VPS35[D620N] mutation induces LRRK2 mediated lysosomal association of RILPL1 and TMEM55B

Pal¹,

Taylor²,

Lam³

et al. 2023

Preprint

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The Parkinsons VPS35[D620N] mutation causes lysosome dysfunction enhancing LRRK2 kinase activity. We find the VPS35[D620N] mutation alters expression of ~350 lysosomal proteins and stimulates LRRK2 phosphorylation of Rab proteins at the lysosome. This recruits the phosphoRab effector protein RILPL1 to the lysosome where it binds to the lysosomal integral membrane protein TMEM55B. We identify highly conserved regions of RILPL1 and TMEM55B that interact and design mutations that block binding. In mouse fibroblasts, brain, and lung, we demonstrate that the VPS35 [D620N] mutation reduces RILPL1 levels, in a manner reversed by LRRK2 inhibition. Knock-out of RILPL1 enhances phosphorylation of Rab substrates and knock-out of TMEM55B increases RILPL1 levels. The lysosomotropic agent LLOMe, also induced LRRK2 kinase mediated association of RILPL1 to the lysosome, but to a lower extent than the D620N mutation. Our study uncovers a pathway through which dysfunctional lysosomes resulting from the VPS35[D620N] mutation recruit and activate LRRK2 on the lysosomal surface, driving assembly of the RILPL1-TMEM55B complex.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Parkinson’s VPS35[D620N] mutation induces LRRK2 mediated lysosomal association of RILPL1 and TMEM55B

Pal¹,

Taylor²,

Lam³

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…We next investigated the levels of the set of lysosomal proteins (cathepsin B, cathepsin C, cathepsin D, cathepsin L, GBA, LAMP1, TFE3 and TFEB) that were previously reported to increase following inhibition or depletion of LRRK2 in macrophages and microglia ( 33 ). In WT versus VPS35[D620N] and VPS35[D620N] ± MLi-2 MEF datasets, only cathepsin L was moderately decreased by the VPS35[D620N] mutation (fig.…”

Section: Resultsmentioning

confidence: 99%

“…At the lysosome, LRRK2 is activated and found to phosphorylate Rab proteins, thereby recruiting JIP4, which promotes formation of tubular structures that release membranous content from lysosomes ( 12 ). Recent work reveals that LRRK2 negatively regulates lysosomal degradative activity in macrophages and microglia via a transcriptional mechanism involving transcription factor E3 (TFE3) ( 33 ). Depletion of LRRK2 and inhibition of LRRK2 kinase activity both enhance lysosomal proteolytic activity and increase the expression of multiple lysosomal hydrolases ( 33 ).…”

Section: Introductionmentioning

confidence: 99%

Parkinson’s VPS35[D620N] mutation induces LRRK2-mediated lysosomal association of RILPL1 and TMEM55B

Pal,

Taylor,

Lam

et al. 2023

Sci. Adv.

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We demonstrate that the Parkinson’s VPS35[D620N] mutation alters the expression of ~220 lysosomal proteins and stimulates recruitment and phosphorylation of Rab proteins at the lysosome. This recruits the phospho-Rab effector protein RILPL1 to the lysosome where it binds to the lysosomal integral membrane protein TMEM55B. We identify highly conserved regions of RILPL1 and TMEM55B that interact and design mutations that block binding. In mouse fibroblasts, brain, and lung, we demonstrate that the VPS35[D620N] mutation reduces RILPL1 levels, in a manner reversed by LRRK2 inhibition and proteasome inhibitors. Knockout of RILPL1 enhances phosphorylation of Rab substrates, and knockout of TMEM55B increases RILPL1 levels. The lysosomotropic agent LLOMe also induced LRRK2 kinase–mediated association of RILPL1 to the lysosome, but to a lower extent than the D620N mutation. Our study uncovers a pathway through which dysfunctional lysosomes resulting from the VPS35[D620N] mutation recruit and activate LRRK2 on the lysosomal surface, driving assembly of the RILPL1-TMEM55B complex.

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“…Restoring TFEB expression has been shown to protect cells from senescence and ameliorate senescence-related pathology in vitro and in vivo (Zhang et al, 2019;Zheng et al, 2019Zheng et al, , 2018Wang et al, 2021). The Parkinson's disease-related gene LRRK2 is recently found to suppress TFEB activation and lysosomal biogenesis, and the genetic deletion or pharmacological inhibition of LRRK2 restored lysosomal abundance and proteolytic activity (Yadavalli & Ferguson, 2023). Spermidine, an endogenous metabolite of polyamine, is reduced in the elderly, whereas its supplementation restores TFEB expression and reverses immune senescence (Zhang et al, 2019).…”

Section: Augmenting Lypas Capacity For Disease Treatment and Healthy ...mentioning

confidence: 99%

Lysosomes in senescence and aging

Tan,

Finkel

2023

EMBO Reports

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Dysfunction of lysosomes, the primary hydrolytic organelles in animal cells, is frequently associated with aging and age‐related diseases. At the cellular level, lysosomal dysfunction is strongly linked to cellular senescence or the induction of cell death pathways. However, the precise mechanisms by which lysosomal dysfunction participates in these various cellular or organismal phenotypes have remained elusive. The ability of lysosomes to degrade diverse macromolecules including damaged proteins and organelles puts lysosomes at the center of multiple cellular stress responses. Lysosomal activity is tightly regulated by many coordinated cellular processes including pathways that function inside and outside of the organelle. Here, we collectively classify these coordinated pathways as the lysosomal processing and adaptation system (LYPAS). We review evidence that the LYPAS is upregulated by diverse cellular stresses, its adaptability regulates senescence and cell death decisions, and it can form the basis for therapeutic manipulation for a wide range of age‐related diseases and potentially for aging itself.

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LRRK2 Suppresses Lysosome Degradative Activity in Macrophages and Microglia Through MiT-TFE Transcription Factor Inhibition

Cited by 12 publications

References 96 publications

Parkinson’s VPS35[D620N] mutation induces LRRK2 mediated lysosomal association of RILPL1 and TMEM55B

Parkinson’s VPS35[D620N] mutation induces LRRK2 mediated lysosomal association of RILPL1 and TMEM55B

Parkinson’s VPS35[D620N] mutation induces LRRK2-mediated lysosomal association of RILPL1 and TMEM55B

Lysosomes in senescence and aging

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