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Opposing actions of JIP4 and RILPL1 provide antagonistic motor force to dynamically regulate membrane reformation during lysosomal tubulation/sorting driven by LRRK2.
Bonet-Ponce, Luis; Tegicho, Tsion; Beilina, Alexandra; Kluss, Jillian H; Li, Yan; Cookson, Mark R.
Afiliación
  • Bonet-Ponce L; Department of Neurology, Wexner Medical Center, The Ohio State University, Columbus, Ohio, 43210, USA.
  • Tegicho T; Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, 20892, USA.
  • Beilina A; Department of Neurology, Wexner Medical Center, The Ohio State University, Columbus, Ohio, 43210, USA.
  • Kluss JH; Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, 20892, USA.
  • Li Y; Cell Biology and Gene Expression Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, 20892, USA.
  • Cookson MR; Proteomic Core Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, 20892, USA.
bioRxiv ; 2024 Apr 03.
Article en En | MEDLINE | ID: mdl-38903076
ABSTRACT
Lysosomes are dynamic cellular structures that adaptively remodel their membrane in response to stimuli, including membrane damage. We previously uncovered a process we term LYTL (LYsosomal Tubulation/sorting driven by Leucine-Rich Repeat Kinase 2 [LRRK2]), wherein damaged lysosomes generate tubules sorted into mobile vesicles. LYTL is orchestrated by the Parkinson's disease-associated kinase LRRK2 that recruits the motor adaptor protein and RHD family member JIP4 to lysosomes via phosphorylated RAB proteins. To identify new players involved in LYTL, we performed unbiased proteomics on isolated lysosomes after LRRK2 kinase inhibition. Our results demonstrate that there is recruitment of RILPL1 to ruptured lysosomes via LRRK2 activity to promote phosphorylation of RAB proteins at the lysosomal surface. RILPL1, which is also a member of the RHD family, enhances the clustering of LRRK2-positive lysosomes in the perinuclear area and causes retraction of LYTL tubules, in contrast to JIP4 which promotes LYTL tubule extension. Mechanistically, RILPL1 binds to p150Glued, a dynactin subunit, facilitating the transport of lysosomes and tubules to the minus end of microtubules. Further characterization of the tubulation process revealed that LYTL tubules move along tyrosinated microtubules, with tubulin tyrosination proving essential for tubule elongation. In summary, our findings emphasize the dynamic regulation of LYTL tubules by two distinct RHD proteins and pRAB effectors, serving as opposing motor adaptor proteins JIP4, promoting tubulation via kinesin, and RILPL1, facilitating tubule retraction through dynein/dynactin. We infer that the two opposing processes generate a metastable lysosomal membrane deformation that facilitates dynamic tubulation events.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos