In autophagy, autophagosomes deliver the lumenal contents to lysosomes for degradation via autophagosome-lysosome fusion. In contrast, autophagosome outer membrane components were recycled via autophagosomal components recycling (ACR), which is mediated by the recycler complex. The recycler complex, composed of SNX4, SNX5, and SNX17, cooperate with the dynein-dynactin complex to mediate ACR. However, how ACR is regulated remains unknown. Here, we found that Rab32 family proteins localize to autolysosomes and are required for ACR, rather than other autophagosomal or lysosomal Rab proteins. The GTPase activity of Rab32 family proteins, governed by their guanine nucleotide exchange factor and GTPase-activating protein, plays a key role in regulating ACR. This regulation occurs through the control of recycler complex formation, as well as the connection between the recycler-cargo and dynactin complex. Together, our study reveals an unidentified Rab32 family-dependent regulatory mechanism for ACR.
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http://dx.doi.org/10.1083/jcb.202306040 | DOI Listing |
Mov Disord
December 2024
Department of Biomedical Sciences, Humanitas University, Milan, Italy.
Background And Objective: Recently, RAB32 has been identified as possibly linked to Parkinson's disease. We studied the prevalence and clinical correlates of the p.Ser71Arg variant in the RAB32 gene in a large case series of Italian patients with Parkinson's disease or atypical parkinsonism.
View Article and Find Full Text PDFNPJ Parkinsons Dis
October 2024
Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
The Parkinson's Families Project is a UK-wide study aimed at identifying genetic variation associated with familial and early-onset Parkinson's disease (PD). We recruited individuals with a clinical diagnosis of PD and age at motor symptom onset ≤45 years and/or a family history of PD in up to third-degree relatives. Where possible, we also recruited affected and unaffected relatives.
View Article and Find Full Text PDFJ Cell Biol
October 2024
Department of Biochemistry and Molecular Biology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Disease, Huazhong University of Science and Technology, Wuhan, China.
How are Rab GTPases regulated during lysosome-related organelle (LRO) biogenesis? Li et al. (https://doi.org/10.
View Article and Find Full Text PDFJ Cell Biol
October 2024
Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, China.
Lysosome-related organelles (LROs) are specialized lysosomes with cell type-specific roles in organismal homeostasis. Dysregulation of LROs leads to many human disorders, but the mechanisms underlying their biogenesis are not fully understood. Here, we identify a group of LYSMD proteins as evolutionarily conserved regulators of LROs.
View Article and Find Full Text PDFNat Genet
July 2024
Department of Neurology, UMass Chan Medical School, Worcester, MA, USA.
Despite substantial progress, causal variants are identified only for a minority of familial Parkinson's disease (PD) cases, leaving high-risk pathogenic variants unidentified. To identify such variants, we uniformly processed exome sequencing data of 2,184 index familial PD cases and 69,775 controls. Exome-wide analyses converged on RAB32 as a novel PD gene identifying c.
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