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xbx-4, a homolog of the Joubert syndrome gene FAM149B1, acts via the CCRK and MAK kinase cascade to regulate cilia morphology

View ORCID ProfileAshish K. Maurya, View ORCID ProfilePiali Sengupta
doi: https://doi.org/10.1101/2021.05.09.443182
Ashish K. Maurya
Department of Biology, Brandeis University, Waltham MA 02454
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  • For correspondence: ashishkm@brandeis.edu sengupta@brandeis.edu
Piali Sengupta
Department of Biology, Brandeis University, Waltham MA 02454
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  • For correspondence: ashishkm@brandeis.edu sengupta@brandeis.edu
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ABSTRACT

Primary cilia are microtubule (MT)-based organelles that mediate sensory functions in multiple cell types. Disruption of cilia structure or function leads to a diverse collection of diseases termed ciliopathies (1–3). Mutations in the DUF3719 domain-containing protein FAM149B1 have recently been shown to elongate cilia via unknown mechanisms and result in the ciliopathy Joubert syndrome (4). The highly conserved CCRK and MAK/RCK kinases negatively regulate cilia length and structure in Chlamydomonas, C. elegans, and mammalian cells (5–11). How the activity of this kinase cascade is tuned to precisely regulate cilia architecture is unclear. Here we identify XBX-4, a DUF3719 domain-containing protein related to human FAM149B1, as a novel regulator of the DYF-18 CCRK and DYF-5 MAK kinase pathway in C. elegans. As in dyf-18 and dyf-5 mutants (11), sensory neuron cilia are elongated in xbx-4 mutants and exhibit altered axonemal MT stability. XBX-4 promotes DYF-18 CCRK activity to regulate DYF-5 MAK function and localization. We find that Joubert syndrome-associated mutations in the XBX-4 DUF3719 domain also elongate cilia in C. elegans. Our results identify a new metazoan-specific regulator of this highly conserved kinase pathway, and suggest that FAM149B1 may similarly act via the CCRK/MAK kinase pathway to regulate ciliary homeostasis in humans.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 10, 2021.
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xbx-4, a homolog of the Joubert syndrome gene FAM149B1, acts via the CCRK and MAK kinase cascade to regulate cilia morphology
Ashish K. Maurya, Piali Sengupta
bioRxiv 2021.05.09.443182; doi: https://doi.org/10.1101/2021.05.09.443182
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xbx-4, a homolog of the Joubert syndrome gene FAM149B1, acts via the CCRK and MAK kinase cascade to regulate cilia morphology
Ashish K. Maurya, Piali Sengupta
bioRxiv 2021.05.09.443182; doi: https://doi.org/10.1101/2021.05.09.443182

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