Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/34667
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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