Trabid patient mutations impede the axonal trafficking of adenomatous polyposis coli to disrupt neurite growth

Author:

Frank Daniel12ORCID,Bergamasco Maria23ORCID,Mlodzianoski Michael J24ORCID,Kueh Andrew2567,Tsui Ellen28ORCID,Hall Cathrine29ORCID,Kastrappis Georgios10,Voss Anne Kathrin23ORCID,McLean Catriona11ORCID,Faux Maree12ORCID,Rogers Kelly L24ORCID,Tran Bang10ORCID,Vincan Elizabeth1013ORCID,Komander David12,Dewson Grant12,Tran Hoanh1210ORCID

Affiliation:

1. Ubiquitin Signalling Division, Walter and Eliza Hall Institute of Medical Research

2. Department of Medical Biology, The University of Melbourne

3. Epigenetics and Development Division, Walter and Eliza Hall Institute of Medical Research

4. Centre for Dynamic Imaging, Walter and Eliza Hall Institute of Medical Research

5. Melbourne Advanced Genome Editing Centre, Walter and Eliza Hall Institute of Medical Research

6. Olivia Newton-John Cancer Research Institute

7. School of Cancer Medicine, La Trobe University

8. Histology Facility, Walter and Eliza Hall Institute of Medical Research

9. Inflammation Division, Walter and Eliza Hall Institute of Medical Research

10. Department of Infectious Diseases, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity

11. Department of Anatomical Pathology, The Alfred Hospital

12. Neuro-Oncology Group, Murdoch Children’s Research Institute

13. The Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at The Peter Doherty Institute for Infection and Immunity

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.

Funder

National Health and Medical Research Council

Bodhi Education Fund

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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