The FAM13A Long Isoform Regulates Cilia Movement and Coordination in Airway Mucociliary Transport. Journal Abstract

The FAM13A Long Isoform Regulates Cilia Movement and Coordination in Airway Mucociliary Transport.

Publication Date: 2024 Sep

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Authors

Ashleigh Howes; Clare Rogerson; Nikolai Belyaev; Tina Karagyozova; Radu Rapiteanu; Ricardo Fradique; Nicola Pellicciotta; David Mayhew; Catherine Hurd; Stefania Crotta; Tanya Singh; Kevin Dingwell; Anniek Myatt; Navot Arad; Hikmatyar Hasan; Hielke Bijlsma; Aliza Panjwani; Vinaya Vijayan; George Young; Angela Bridges; Sebastien Petit-Frere; Joanna Betts; Chris Larminie; James C Smith; Edith M Hessel; David Michalovich; Louise Walport; Pietro Cicuta; Andrew J Powell; Soren Beinke; Andreas Wack

Abstract

OBJECTIVE

Single nucelotide polymorphisms (SNPs) at the locus are among the most commonly reported risk alleles associated with chronic obstructive pulmonary disease (COPD) and other respiratory diseases; however, the physiological role of FAM13A is unclear. In humans, two major protein isoforms are expressed at the locus: "long" and "short," but their functions remain unknown, partly because of a lack of isoform conservation in mice. We performed in-depth characterization of organotypic primary human airway epithelial cell subsets and show that multiciliated cells predominantly express the FAM13A long isoform containing a putative N-terminal Rho GTPase-activating protein (RhoGAP) domain. Using purified proteins, we directly demonstrate the RhoGAP activity of this domain. In , which conserve the long-isoform, Fam13a deficiency impaired cilia-dependent embryo motility. In human primary epithelial cells, long-isoform deficiency did not affect multiciliogenesis but reduced cilia coordination in mucociliary transport assays. This is the first demonstration that FAM13A isoforms are differentially expressed within the airway epithelium, with implications for the assessment and interpretation of SNP effects on expression levels. We also show that the long FAM13A isoform coordinates cilia-driven movement, suggesting that risk alleles may affect susceptibility to respiratory diseases through deficiencies in mucociliary clearance.

Source

American journal of respiratory cell and molecular biology

Pub Types(s)

Journal Article

Language

English

PubMed ID

38691660