KDM3A coordinates actin dynamics with intraflagellar transport to regulate cilia stability

Patricia L Yeyati; Rachel Schiller; Girish Mali; Ioannis Kasioulis; Akane Kawamura; Ian R Adams; Christopher Playfoot; Nick Gilbert; Veronica van Heyningen; Jimi Wills; Alex von Kriegsheim; Andrew Finch; Juro Sakai; Christopher J Schofield; Ian J Jackson; Pleasantine Mill

doi:10.1083/jcb.201607032

KDM3A coordinates actin dynamics with intraflagellar transport to regulate cilia stability

Patricia L Yeyati, Rachel Schiller, Girish Mali, Ioannis Kasioulis, Akane Kawamura, Ian R Adams, Christopher Playfoot, Nick Gilbert, Veronica van Heyningen, Jimi Wills, Alex von Kriegsheim, Andrew Finch, Juro Sakai, Christopher J Schofield, Ian J Jackson, Pleasantine Mill^*

^*Corresponding author for this work

School of Biochemistry

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	999-1013
Number of pages	15
Journal	The Journal of cell biology
Volume	216
Issue number	4
DOIs	https://doi.org/10.1083/jcb.201607032
Publication status	Published - 3 Apr 2017

Bibliographical note

Keywords

Actins/metabolism
Animals
Biological Transport/physiology
Cell Line
Cilia/metabolism
Flagella/metabolism
Gene Expression/physiology
Histone Demethylases/metabolism
Humans
Jumonji Domain-Containing Histone Demethylases/metabolism
Mice
Morphogenesis/physiology
Mutation/physiology
Phenotype

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Yeyati, P. L., Schiller, R., Mali, G., Kasioulis, I., Kawamura, A., Adams, I. R., Playfoot, C., Gilbert, N., van Heyningen, V., Wills, J., von Kriegsheim, A., Finch, A., Sakai, J., Schofield, C. J., Jackson, I. J., & Mill, P. (2017). KDM3A coordinates actin dynamics with intraflagellar transport to regulate cilia stability. The Journal of cell biology, 216(4), 999-1013. https://doi.org/10.1083/jcb.201607032

@article{99296957df164da29a4a5d8e37197796,

title = "KDM3A coordinates actin dynamics with intraflagellar transport to regulate cilia stability",

abstract = "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.",

keywords = "Actins/metabolism, Animals, Biological Transport/physiology, Cell Line, Cilia/metabolism, Flagella/metabolism, Gene Expression/physiology, Histone Demethylases/metabolism, Humans, Jumonji Domain-Containing Histone Demethylases/metabolism, Mice, Morphogenesis/physiology, Mutation/physiology, Phenotype",

author = "Yeyati, {Patricia L} and Rachel Schiller and Girish Mali and Ioannis Kasioulis and Akane Kawamura and Adams, {Ian R} and Christopher Playfoot and Nick Gilbert and {van Heyningen}, Veronica and Jimi Wills and {von Kriegsheim}, Alex and Andrew Finch and Juro Sakai and Schofield, {Christopher J} and Jackson, {Ian J} and Pleasantine Mill",

note = "{\textcopyright} 2017 Yeyati et al.",

year = "2017",

month = apr,

day = "3",

doi = "10.1083/jcb.201607032",

language = "English",

volume = "216",

pages = "999--1013",

journal = "The Journal of cell biology",

issn = "0021-9525",

publisher = "Rockefeller University Press",

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Yeyati, PL, Schiller, R, Mali, G, Kasioulis, I, Kawamura, A, Adams, IR, Playfoot, C, Gilbert, N, van Heyningen, V, Wills, J, von Kriegsheim, A, Finch, A, Sakai, J, Schofield, CJ, Jackson, IJ & Mill, P 2017, 'KDM3A coordinates actin dynamics with intraflagellar transport to regulate cilia stability', The Journal of cell biology, vol. 216, no. 4, pp. 999-1013. https://doi.org/10.1083/jcb.201607032

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

PY - 2017/4/3

Y1 - 2017/4/3

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.

KW - Actins/metabolism

KW - Animals

KW - Biological Transport/physiology

KW - Cell Line

KW - Cilia/metabolism

KW - Flagella/metabolism

KW - Gene Expression/physiology

KW - Histone Demethylases/metabolism

KW - Humans

KW - Jumonji Domain-Containing Histone Demethylases/metabolism

KW - Mice

KW - Morphogenesis/physiology

KW - Mutation/physiology

KW - Phenotype

U2 - 10.1083/jcb.201607032

DO - 10.1083/jcb.201607032

M3 - Article (Academic Journal)

C2 - 28246120

SN - 0021-9525

VL - 216

SP - 999

EP - 1013

JO - The Journal of cell biology

JF - The Journal of cell biology

IS - 4

ER -

KDM3A coordinates actin dynamics with intraflagellar transport to regulate cilia stability

Abstract

Bibliographical note

Keywords

UN SDGs

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