ArticleCurrent biology : CB2021
ARL8 Relieves SKIP Autoinhibition to Enable Coupling of Lysosomes to Kinesin-1.
Article in Current biology : CB, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 67 citations in OpenAlex.
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- Activation of Lysosomal Retrograde Transport Triggers TPC1-IP3R1 CaAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- BLOC-1 and BORC: Complex regulators of endolysosomal dynamics.Cell chemical biology · 2025Review
- OSBP Participates in Neural Damage Repair by Regulating Lysosome Transport Under Oxidative Stress.Molecular neurobiology · 2025Article
- KIF9 Ameliorates Neuropathology and Cognitive Dysfunction by Promoting Macroautophagy in a Mouse Model of Alzheimer's Disease.Aging cell · 2025Article
- RPL41 inhibits the proliferation and migration of retinoblastoma through the ARL5B-associated lysosomal trafficking.Frontiers in immunology · 2025Article
- Altered expression of vesicular trafficking machinery in prostate cancer affects lysosomal dynamics and provides insight into the underlying biology and disease progression.British journal of cancer · 2024Article
- An initial HOPS-mediated fusion event is critical for autophagosome transport initiation from the axon terminal.Autophagy · 2024Article
- Septin-coated microtubules promote maturation of multivesicular bodies by inhibiting their motility.The Journal of cell biology · 2024Article
- Plekhm2 acts as an autophagy modulator in murine heart and cardiofibroblasts.Scientific reports · 2024Article
- Kinesin Regulation in the Proximal Axon is Essential for Dendrite-selective Transport.Molecular biology of the cell · 2024Article
- Polarized transport requires AP-1-mediated recruitment of KIF13A and KIF13B at the trans-Golgi.Molecular biology of the cell · 2024Article
- PLEKHM2 deficiency induces impaired mitochondrial clearance and elevated ROS levels in human iPSC-derived cardiomyocytes.Cell death discovery · 2024Article
- DENND6A links Arl8b to a Rab34/RILP/dynein complex, regulating lysosomal positioning and autophagy.Nature communications · 2024Article
- Amphetamine Induces Sex-Dependent Loss of the Striatal Dopamine Transporter in Sensitized Mice.eNeuro · 2024Article
- Axonal transport of autophagosomes is regulated by dynein activators JIP3/JIP4 and ARF/RAB GTPases.The Journal of cell biology · 2023Article
- Presynaptic Precursor Vesicles-Cargo, Biogenesis, and Kinesin-Based Transport across Species.Cells · 2023Review
- A proteomics analysis of 5xFAD mouse brain regions reveals the lysosome-associated protein Arl8b as a candidate biomarker for Alzheimer's disease.Genome medicine · 2023Article
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
Long-range movement of organelles within the cytoplasm relies on coupling to microtubule motors, a process that is often mediated by adaptor proteins. In many cases, this coupling involves organelle- or adaptor-induced activation of the microtubule motors by conformational reversal of an autoinhibited state. Herein, we show that a similar regulatory mechanism operates for an adaptor protein named SKIP (also known as PLEKHM2). SKIP binds to the small guanosine triphosphatase (GTPase) ARL8 on the lysosomal membrane to couple lysosomes to the anterograde microtubule motor kinesin-1. Structure-function analyses of SKIP reveal that the C-terminal region comprising three pleckstrin homology (PH) domains interacts with the N-terminal region comprising ARL8- and kinesin-1-binding sites. This interaction inhibits coupling of lysosomes to kinesin-1 and, consequently, lysosome movement toward the cell periphery. We also find that ARL8 does not just recruit SKIP to the lysosomal membrane but also relieves SKIP autoinhibition, promoting kinesin-1-driven, anterograde lysosome transport. Finally, our analyses show that the largely disordered middle region of SKIP mediates self-association and that this self-association enhances the interaction of SKIP with kinesin-1. These findings indicate that SKIP is not just a passive connector of lysosome-bound ARL8 to kinesin-1 but is itself subject to intra- and inter-molecular interactions that regulate its function. We anticipate that similar organelle- or GTPase-induced conformational changes could regulate the activity of other kinesin adaptors.
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