Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth
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 f...
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eLife Sciences Publications Ltd
2023-12-01
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Online Access: | https://elifesciences.org/articles/90796 |
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author | Daniel Frank Maria Bergamasco Michael J Mlodzianoski Andrew Kueh Ellen Tsui Cathrine Hall Georgios Kastrappis Anne Kathrin Voss Catriona McLean Maree Faux Kelly L Rogers Bang Tran Elizabeth Vincan David Komander Grant Dewson Hoanh Tran |
author_facet | Daniel Frank Maria Bergamasco Michael J Mlodzianoski Andrew Kueh Ellen Tsui Cathrine Hall Georgios Kastrappis Anne Kathrin Voss Catriona McLean Maree Faux Kelly L Rogers Bang Tran Elizabeth Vincan David Komander Grant Dewson Hoanh Tran |
author_sort | Daniel Frank |
collection | DOAJ |
description | 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. |
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language | English |
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spelling | doaj.art-11cef469c8eb42c9944ccee57a624fbc2023-12-15T12:56:26ZengeLife Sciences Publications LtdeLife2050-084X2023-12-011210.7554/eLife.90796Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growthDaniel Frank0https://orcid.org/0000-0003-4998-2220Maria Bergamasco1https://orcid.org/0000-0003-3322-9701Michael J Mlodzianoski2https://orcid.org/0000-0002-3510-9167Andrew Kueh3Ellen Tsui4https://orcid.org/0009-0005-7340-7412Cathrine Hall5https://orcid.org/0009-0005-1004-9435Georgios Kastrappis6Anne Kathrin Voss7https://orcid.org/0000-0002-3853-9381Catriona McLean8https://orcid.org/0000-0002-0302-5727Maree Faux9https://orcid.org/0000-0001-7770-6683Kelly L Rogers10https://orcid.org/0000-0002-6755-0221Bang Tran11https://orcid.org/0000-0002-3108-8805Elizabeth Vincan12https://orcid.org/0000-0002-8607-4849David Komander13Grant Dewson14Hoanh Tran15https://orcid.org/0000-0002-0176-4112Ubiquitin Signalling Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, The University of Melbourne, Parkville, AustraliaDepartment of Medical Biology, The University of Melbourne, Parkville, Australia; Epigenetics and Development Division, Walter and Eliza Hall Institute of Medical Research, Parkville, AustraliaDepartment of Medical Biology, The University of Melbourne, Parkville, Australia; Centre for Dynamic Imaging, Walter and Eliza Hall Institute of Medical Research, Parkville, AustraliaDepartment of Medical Biology, The University of Melbourne, Parkville, Australia; Melbourne Advanced Genome Editing Centre, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Olivia Newton-John Cancer Research Institute, Heidelberg, Australia; School of Cancer Medicine, La Trobe University, Heidelberg, AustraliaDepartment of Medical Biology, The University of Melbourne, Parkville, Australia; Histology Facility, Walter and Eliza Hall Institute of Medical Research, Parkville, AustraliaDepartment of Medical Biology, The University of Melbourne, Parkville, Australia; Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, AustraliaDepartment of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, AustraliaDepartment of Medical Biology, The University of Melbourne, Parkville, Australia; Epigenetics and Development Division, Walter and Eliza Hall Institute of Medical Research, Parkville, AustraliaDepartment of Anatomical Pathology, The Alfred Hospital, Melbourne, AustraliaNeuro-Oncology Group, Murdoch Children’s Research Institute, Parkville, AustraliaDepartment of Medical Biology, The University of Melbourne, Parkville, Australia; Centre for Dynamic Imaging, Walter and Eliza Hall Institute of Medical Research, Parkville, AustraliaDepartment of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, AustraliaDepartment of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia; The Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at The Peter Doherty Institute for Infection and Immunity, Melbourne, AustraliaUbiquitin Signalling Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, The University of Melbourne, Parkville, AustraliaUbiquitin Signalling Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, The University of Melbourne, Parkville, AustraliaUbiquitin Signalling Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Australia; Department of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, AustraliaZRANB1 (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.https://elifesciences.org/articles/90796adenomatous polyposis colineurodevelopmentZRANB1TrabidSTRIPAKaxonal protein trafficking |
spellingShingle | Daniel Frank Maria Bergamasco Michael J Mlodzianoski Andrew Kueh Ellen Tsui Cathrine Hall Georgios Kastrappis Anne Kathrin Voss Catriona McLean Maree Faux Kelly L Rogers Bang Tran Elizabeth Vincan David Komander Grant Dewson Hoanh Tran Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth eLife adenomatous polyposis coli neurodevelopment ZRANB1 Trabid STRIPAK axonal protein trafficking |
title | Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth |
title_full | Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth |
title_fullStr | Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth |
title_full_unstemmed | Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth |
title_short | Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth |
title_sort | trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth |
topic | adenomatous polyposis coli neurodevelopment ZRANB1 Trabid STRIPAK axonal protein trafficking |
url | https://elifesciences.org/articles/90796 |
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