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Title: | Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth. | Austin Authors: | Frank, Daniel;Bergamasco, Maria;Mlodzianoski, Michael J;Kueh, Andrew;Tsui, Ellen;Hall, Cathrine;Kastrappis, Georgios;Voss, Anne Kathrin;McLean, Catriona;Faux, Maree;Rogers, Kelly L;Tran, Bang;Vincan, Elizabeth;Komander, David;Dewson, Grant;Tran, Hoanh | Affiliation: | Ubiquitin Signalling Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.;Department of Medical Biology, The University of Melbourne, Parkville, Australia. Department of Medical Biology, The University of Melbourne, Parkville, Australia.;Epigenetics and Development Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia. Department of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia. Department of Anatomical Pathology, The Alfred Hospital, Melbourne, Australia. Neuro-Oncology Group, Murdoch Children's Research Institute, Parkville, Australia. Department of Medical Biology, The University of Melbourne, Parkville, Australia.;Centre for Dynamic Imaging, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia. Olivia Newton-John Cancer Research Institute |
Issue Date: | 15-Dec-2023 | Date: | 2023 | Publication information: | eLife 2023-12-15; 12 | Abstract: | ZRANB1 (human Trabid) missense mutations have been identified in children diagnosed with a range of congenital disorders including reduced brain size, but how Trabid regulates neurodevelopment is not understood. We have characterized these patient mutations in cells and mice to identify a key role for Trabid in the regulation of neurite growth. One of the patient mutations flanked the catalytic cysteine of Trabid and its deubiquitylating (DUB) activity was abrogated. The second variant retained DUB activity, but failed to bind STRIPAK, a large multiprotein assembly implicated in cytoskeleton organization and neural development. Zranb1 knock-in mice harboring either of these patient mutations exhibited reduced neuronal and glial cell densities in the brain and a motor deficit consistent with fewer dopaminergic neurons and projections. Mechanistically, both DUB-impaired and STRIPAK-binding-deficient Trabid variants impeded the trafficking of adenomatous polyposis coli (APC) to microtubule plus-ends. Consequently, the formation of neuronal growth cones and the trajectory of neurite outgrowth from mutant midbrain progenitors were severely compromised. We propose that STRIPAK recruits Trabid to deubiquitylate APC, and that in cells with mutant Trabid, APC becomes hyperubiquitylated and mislocalized causing impaired organization of the cytoskeleton that underlie the neuronal and developmental phenotypes. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/34667 | DOI: | 10.7554/eLife.90796 | ORCID: | 0000-0003-4998-2220 0000-0003-3322-9701 0000-0002-3510-9167 0009-0005-7340-7412 0009-0005-1004-9435 0000-0002-3853-9381 0000-0002-0302-5727 0000-0001-7770-6683 0000-0002-6755-0221 0000-0002-3108-8805 0000-0002-8607-4849 0000-0002-0176-4112 |
Journal: | eLife | PubMed URL: | 38099646 | ISSN: | 2050-084X | Type: | Journal Article | Subjects: | STRIPAK Trabid ZRANB1 adenomatous polyposis coli axon elongation axon guidance axonal protein trafficking cell biology cytoskeleton organization deubiquitylating enzyme human microcephaly mouse neurocristopathies neurodevelopment neuroscience polarized cell migration Adenomatous Polyposis Coli/metabolism Adenomatous Polyposis Coli Protein/genetics Adenomatous Polyposis Coli Protein/metabolism Axons/metabolism Neurites/metabolism |
Appears in Collections: | Journal articles |
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