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Loss of an extensive ciliary connectome induces proteostasis and cell fate switching in a severe motile ciliopathy.
Brody, Steven L; Pan, Jiehong; Huang, Tao; Xu, Jian; Xu, Huihui; Koenitizer, Jeffrey; Brennan, Steven K; Nanjundappa, Rashmi; Saba, Thomas G; Berical, Andrew; Hawkins, Finn J; Wang, Xiangli; Zhang, Rui; Mahjoub, Moe R; Horani, Amjad; Dutcher, Susan K.
Afiliação
  • Brody SL; Department of Medicine, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
  • Pan J; Department of Medicine, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
  • Huang T; Department of Medicine, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
  • Xu J; Department of Medicine, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
  • Xu H; Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
  • Koenitizer J; Department of Medicine, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
  • Brennan SK; Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
  • Nanjundappa R; Department of Medicine, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
  • Saba TG; Department of Pediatrics, University of Michigan, Ann Arbor, MI, 48108, USA.
  • Berical A; Center for Regenerative Medicine, Boston University, Boston, MA, 02118, USA.
  • Hawkins FJ; Center for Regenerative Medicine, Boston University, Boston, MA, 02118, USA.
  • Wang X; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
  • Zhang R; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
  • Mahjoub MR; Department of Medicine, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
  • Horani A; Department of Cell Biology and Physisology, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
  • Dutcher SK; Department of Pediatrics, University of Michigan, Ann Arbor, MI, 48108, USA.
bioRxiv ; 2024 Mar 21.
Article em En | MEDLINE | ID: mdl-38562900
ABSTRACT
Motile cilia have essential cellular functions in development, reproduction, and homeostasis. Genetic causes for motile ciliopathies have been identified, but the consequences on cellular functions beyond impaired motility remain unknown. Variants in CCDC39 and CCDC40 cause severe disease not explained by loss of motility. Using human cells with pathological variants in these genes, Chlamydomonas genetics, cryo-electron microscopy, single cell RNA transcriptomics, and proteomics, we identified perturbations in multiple cilia-independent pathways. Absence of the axonemal CCDC39/CCDC40 heterodimer results in loss of a connectome of over 90 proteins. The undocked connectome activates cell quality control pathways, switches multiciliated cell fate, impairs microtubule architecture, and creates a defective periciliary barrier. Both cilia-dependent and independent defects are likely responsible for the disease severity. Our findings provide a foundation for reconsidering the broad cellular impact of pathologic variants in ciliopathies and suggest new directions for therapies.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article