TY - JOUR
T1 - KDM3A coordinates actin dynamics with intraflagellar transport to regulate cilia stability
AU - Yeyati, Patricia L.
AU - Schiller, Rachel
AU - Mali, Girish
AU - Kasioulis, Ioannis
AU - Kawamura, Akane
AU - Adams, Ian R.
AU - Playfoot, Christopher
AU - Gilbert, Nick
AU - van Heyningen, Veronica
AU - Wills, Jimi
AU - von Kriegsheim, Alex
AU - Finch, Andrew
AU - Sakai, Juro
AU - Schofield, Christopher J.
AU - Jackson, Ian J.
AU - Mill, Pleasantine
N1 - Funding Information:
We thank the Structural Genomics Consortium (Oxford) for assistance in protein purification for catalytic studies and the Institute of Genetics and Molecular Medicine technical staff for support with animal husbandry, imaging, and sequencing. We also thank Georgios Kanellos and Brad J. Nolen for expert advice. C.J. Schofield thanks Cancer Research UK and the Wellcome Trust for funding. This work was supported by core funding from the Medical Research Council (MC_UU_12018/26; P.L. Yeyati, G. Mali, I. Kasioulis, and P. Mill).
Publisher Copyright:
© 2017 Yeyati et al.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - Cilia assembly and disassembly are coupled to actin dynamics, ensuring a coherent cellular response during environmental change. How these processes are integrated remains undefined. The histone lysine demethylase KDM3A plays important roles in organismal homeostasis. Loss-of-function mouse models of Kdm3a phenocopy features associated with human ciliopathies, whereas human somatic mutations correlate with poor cancer prognosis. We demonstrate that absence of KDM3A facilitates ciliogenesis, but these resulting cilia have an abnormally wide range of axonemal lengths, delaying disassembly and accumulating intraflagellar transport (IFT) proteins. KDM3A plays a dual role by regulating actin gene expression and binding to the actin cytoskeleton, creating a responsive "actin gate" that involves ARP2/3 activity and IFT. Promoting actin filament formation rescues KDM3A mutant ciliary defects. Conversely, the simultaneous depolymerization of actin networks and IFT overexpression mimics the abnormal ciliary traits of KDM3A mutants. KDM3A is thus a negative regulator of ciliogenesis required for the controlled recruitment of IFT proteins into cilia through the modulation of actin dynamics.
AB - Cilia assembly and disassembly are coupled to actin dynamics, ensuring a coherent cellular response during environmental change. How these processes are integrated remains undefined. The histone lysine demethylase KDM3A plays important roles in organismal homeostasis. Loss-of-function mouse models of Kdm3a phenocopy features associated with human ciliopathies, whereas human somatic mutations correlate with poor cancer prognosis. We demonstrate that absence of KDM3A facilitates ciliogenesis, but these resulting cilia have an abnormally wide range of axonemal lengths, delaying disassembly and accumulating intraflagellar transport (IFT) proteins. KDM3A plays a dual role by regulating actin gene expression and binding to the actin cytoskeleton, creating a responsive "actin gate" that involves ARP2/3 activity and IFT. Promoting actin filament formation rescues KDM3A mutant ciliary defects. Conversely, the simultaneous depolymerization of actin networks and IFT overexpression mimics the abnormal ciliary traits of KDM3A mutants. KDM3A is thus a negative regulator of ciliogenesis required for the controlled recruitment of IFT proteins into cilia through the modulation of actin dynamics.
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U2 - 10.1083/jcb.201607032
DO - 10.1083/jcb.201607032
M3 - Article
C2 - 28246120
AN - SCOPUS:85021851177
SN - 0021-9525
VL - 216
SP - 999
EP - 1013
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 4
ER -
