TY - JOUR
T1 - The FAM13A Long Isoform Regulates Cilia Movement and Co-ordination in Airway Mucociliary Transport
AU - Howes, Ashleigh
AU - Rogerson, Clare
AU - Belyaev, Nikolai
AU - Karagyozova, Tina
AU - Rapiteanu, Radu
AU - Fradique, Ricardo
AU - Pellicciotta, Nicola
AU - Mayhew, David
AU - Hurd, Catherine
AU - Crotta, Stefania
AU - Singh, Tanya
AU - Dingwell, Kevin
AU - Myatt, Anniek
AU - Arad, Navot
AU - Hasan, Hikmatyar
AU - Bijlsma, Hielke
AU - Panjwani, Aliza
AU - Vijayan, Vinaya
AU - Young, George
AU - Bridges, Angela
AU - Petit-Frere, Sebastien
AU - Betts, Joanna
AU - Larminie, Chris
AU - Michalovich, David
AU - Walport, Louise
AU - Cicuta, Pietro
AU - Powell, Andrew J.
AU - Beinke, Soren
AU - Wack, Andreas
PY - 2024/5/1
Y1 - 2024/5/1
N2 - SNPs in the FAM13A locus are amongst 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 FAM13A locus: ‘long’ and ‘short’, but their functions remain unknown, partly due to a lack of isoform conservation in mice. We performed in-depth characterisation 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 RhoGAP activity of this domain. In Xenopus laevis, 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 co-ordination 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 FAM13A expression levels. We also show that the long FAM13A isoform co-ordinates cilia-driven movement, suggesting that FAM13A risk alleles may affect susceptibility to respiratory diseases through deficiencies in mucociliary clearance.
AB - SNPs in the FAM13A locus are amongst 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 FAM13A locus: ‘long’ and ‘short’, but their functions remain unknown, partly due to a lack of isoform conservation in mice. We performed in-depth characterisation 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 RhoGAP activity of this domain. In Xenopus laevis, 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 co-ordination 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 FAM13A expression levels. We also show that the long FAM13A isoform co-ordinates cilia-driven movement, suggesting that FAM13A risk alleles may affect susceptibility to respiratory diseases through deficiencies in mucociliary clearance.
U2 - 10.1165/rcmb.2024-0063oc
DO - 10.1165/rcmb.2024-0063oc
M3 - Article
SN - 1535-4989
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
ER -