HEATR2 Plays a Conserved Role in Assembly of the Ciliary Motile Apparatus

Christine P. Diggle; Daniel J. Moore; Girish Mali; Petra zur Lage; Aouatef Ait-Lounis; Miriam Schmidts; Amelia Shoemark; Amaya Garcia-Munoz; Mihail R. Halachev; Philippe Gautier; Patricia L. Yeyati; David T. Bonthron; Ian M. Carr; Bruce Hayward; Alexander F. Markham; Jilly E. Hope; Alex von Kriegsheim; Hannah M. Mitchison; Ian J. Jackson; Bénédicte Durand; Walter Reith; Eamonn Sheridan; Andrew P. Jarman; Pleasantine Mill

doi:10.1371/journal.pgen.1004577

HEATR2 Plays a Conserved Role in Assembly of the Ciliary Motile Apparatus

Christine P. Diggle, Daniel J. Moore, Girish Mali, Petra zur Lage, Aouatef Ait-Lounis, Miriam Schmidts, Amelia Shoemark, Amaya Garcia-Munoz, Mihail R. Halachev, Philippe Gautier, Patricia L. Yeyati, David T. Bonthron, Ian M. Carr, Bruce Hayward, Alexander F. Markham, Jilly E. Hope, Alex von Kriegsheim, Hannah M. Mitchison, Ian J. Jackson, Bénédicte DurandWalter Reith, Eamonn Sheridan (Lead / Corresponding author), Andrew P. Jarman (Lead / Corresponding author), Pleasantine Mill (Lead / Corresponding author)

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Abstract

Cilia are highly conserved microtubule-based structures that perform a variety of sensory and motility functions during development and adult homeostasis. In humans, defects specifically affecting motile cilia lead to chronic airway infections, infertility and laterality defects in the genetically heterogeneous disorder Primary Ciliary Dyskinesia (PCD). Using the comparatively simple Drosophila system, in which mechanosensory neurons possess modified motile cilia, we employed a recently elucidated cilia transcriptional RFX-FOX code to identify novel PCD candidate genes. Here, we report characterization of CG31320/HEATR2, which plays a conserved critical role in forming the axonemal dynein arms required for ciliary motility in both flies and humans. Inner and outer arm dyneins are absent from axonemes of CG31320 mutant flies and from PCD individuals with a novel splice-acceptor HEATR2 mutation. Functional conservation of closely arranged RFX-FOX binding sites upstream of HEATR2 orthologues may drive higher cytoplasmic expression of HEATR2 during early motile ciliogenesis. Immunoprecipitation reveals HEATR2 interacts with DNAI2, but not HSP70 or HSP90, distinguishing it from the client/chaperone functions described for other cytoplasmic proteins required for dynein arm assembly such as DNAAF1-4. These data implicate CG31320/HEATR2 in a growing intracellular pre-assembly and transport network that is necessary to deliver functional dynein machinery to the ciliary compartment for integration into the motile axoneme.

Original language	English
Article number	e1004577
Number of pages	20
Journal	PLoS Genetics
Volume	10
Issue number	9
DOIs	https://doi.org/10.1371/journal.pgen.1004577
Publication status	Published - 18 Sept 2014

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Molecular Biology
Genetics
Genetics(clinical)
Cancer Research

UN SDGs

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

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Diggle, C. P., Moore, D. J., Mali, G., zur Lage, P., Ait-Lounis, A., Schmidts, M., Shoemark, A., Garcia-Munoz, A., Halachev, M. R., Gautier, P., Yeyati, P. L., Bonthron, D. T., Carr, I. M., Hayward, B., Markham, A. F., Hope, J. E., von Kriegsheim, A., Mitchison, H. M., Jackson, I. J., ... Mill, P. (2014). HEATR2 Plays a Conserved Role in Assembly of the Ciliary Motile Apparatus. PLoS Genetics, 10(9), Article e1004577. https://doi.org/10.1371/journal.pgen.1004577

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title = "HEATR2 Plays a Conserved Role in Assembly of the Ciliary Motile Apparatus",

abstract = "Cilia are highly conserved microtubule-based structures that perform a variety of sensory and motility functions during development and adult homeostasis. In humans, defects specifically affecting motile cilia lead to chronic airway infections, infertility and laterality defects in the genetically heterogeneous disorder Primary Ciliary Dyskinesia (PCD). Using the comparatively simple Drosophila system, in which mechanosensory neurons possess modified motile cilia, we employed a recently elucidated cilia transcriptional RFX-FOX code to identify novel PCD candidate genes. Here, we report characterization of CG31320/HEATR2, which plays a conserved critical role in forming the axonemal dynein arms required for ciliary motility in both flies and humans. Inner and outer arm dyneins are absent from axonemes of CG31320 mutant flies and from PCD individuals with a novel splice-acceptor HEATR2 mutation. Functional conservation of closely arranged RFX-FOX binding sites upstream of HEATR2 orthologues may drive higher cytoplasmic expression of HEATR2 during early motile ciliogenesis. Immunoprecipitation reveals HEATR2 interacts with DNAI2, but not HSP70 or HSP90, distinguishing it from the client/chaperone functions described for other cytoplasmic proteins required for dynein arm assembly such as DNAAF1-4. These data implicate CG31320/HEATR2 in a growing intracellular pre-assembly and transport network that is necessary to deliver functional dynein machinery to the ciliary compartment for integration into the motile axoneme.",

author = "Diggle, {Christine P.} and Moore, {Daniel J.} and Girish Mali and {zur Lage}, Petra and Aouatef Ait-Lounis and Miriam Schmidts and Amelia Shoemark and Amaya Garcia-Munoz and Halachev, {Mihail R.} and Philippe Gautier and Yeyati, {Patricia L.} and Bonthron, {David T.} and Carr, {Ian M.} and Bruce Hayward and Markham, {Alexander F.} and Hope, {Jilly E.} and {von Kriegsheim}, Alex and Mitchison, {Hannah M.} and Jackson, {Ian J.} and B{\'e}n{\'e}dicte Durand and Walter Reith and Eamonn Sheridan and Jarman, {Andrew P.} and Pleasantine Mill",

note = "Publisher Copyright: {\textcopyright} 2014 Diggle et al.",

year = "2014",

month = sep,

day = "18",

doi = "10.1371/journal.pgen.1004577",

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Diggle, CP, Moore, DJ, Mali, G, zur Lage, P, Ait-Lounis, A, Schmidts, M, Shoemark, A, Garcia-Munoz, A, Halachev, MR, Gautier, P, Yeyati, PL, Bonthron, DT, Carr, IM, Hayward, B, Markham, AF, Hope, JE, von Kriegsheim, A, Mitchison, HM, Jackson, IJ, Durand, B, Reith, W, Sheridan, E, Jarman, AP & Mill, P 2014, 'HEATR2 Plays a Conserved Role in Assembly of the Ciliary Motile Apparatus', PLoS Genetics, vol. 10, no. 9, e1004577. https://doi.org/10.1371/journal.pgen.1004577

TY - JOUR

T1 - HEATR2 Plays a Conserved Role in Assembly of the Ciliary Motile Apparatus

AU - Diggle, Christine P.

AU - Moore, Daniel J.

AU - Mali, Girish

AU - zur Lage, Petra

AU - Ait-Lounis, Aouatef

AU - Schmidts, Miriam

AU - Shoemark, Amelia

AU - Garcia-Munoz, Amaya

AU - Halachev, Mihail R.

AU - Gautier, Philippe

AU - Yeyati, Patricia L.

AU - Bonthron, David T.

AU - Carr, Ian M.

AU - Hayward, Bruce

AU - Markham, Alexander F.

AU - Hope, Jilly E.

AU - von Kriegsheim, Alex

AU - Mitchison, Hannah M.

AU - Jackson, Ian J.

AU - Durand, Bénédicte

AU - Reith, Walter

AU - Sheridan, Eamonn

AU - Jarman, Andrew P.

AU - Mill, Pleasantine

PY - 2014/9/18

Y1 - 2014/9/18

N2 - Cilia are highly conserved microtubule-based structures that perform a variety of sensory and motility functions during development and adult homeostasis. In humans, defects specifically affecting motile cilia lead to chronic airway infections, infertility and laterality defects in the genetically heterogeneous disorder Primary Ciliary Dyskinesia (PCD). Using the comparatively simple Drosophila system, in which mechanosensory neurons possess modified motile cilia, we employed a recently elucidated cilia transcriptional RFX-FOX code to identify novel PCD candidate genes. Here, we report characterization of CG31320/HEATR2, which plays a conserved critical role in forming the axonemal dynein arms required for ciliary motility in both flies and humans. Inner and outer arm dyneins are absent from axonemes of CG31320 mutant flies and from PCD individuals with a novel splice-acceptor HEATR2 mutation. Functional conservation of closely arranged RFX-FOX binding sites upstream of HEATR2 orthologues may drive higher cytoplasmic expression of HEATR2 during early motile ciliogenesis. Immunoprecipitation reveals HEATR2 interacts with DNAI2, but not HSP70 or HSP90, distinguishing it from the client/chaperone functions described for other cytoplasmic proteins required for dynein arm assembly such as DNAAF1-4. These data implicate CG31320/HEATR2 in a growing intracellular pre-assembly and transport network that is necessary to deliver functional dynein machinery to the ciliary compartment for integration into the motile axoneme.

AB - Cilia are highly conserved microtubule-based structures that perform a variety of sensory and motility functions during development and adult homeostasis. In humans, defects specifically affecting motile cilia lead to chronic airway infections, infertility and laterality defects in the genetically heterogeneous disorder Primary Ciliary Dyskinesia (PCD). Using the comparatively simple Drosophila system, in which mechanosensory neurons possess modified motile cilia, we employed a recently elucidated cilia transcriptional RFX-FOX code to identify novel PCD candidate genes. Here, we report characterization of CG31320/HEATR2, which plays a conserved critical role in forming the axonemal dynein arms required for ciliary motility in both flies and humans. Inner and outer arm dyneins are absent from axonemes of CG31320 mutant flies and from PCD individuals with a novel splice-acceptor HEATR2 mutation. Functional conservation of closely arranged RFX-FOX binding sites upstream of HEATR2 orthologues may drive higher cytoplasmic expression of HEATR2 during early motile ciliogenesis. Immunoprecipitation reveals HEATR2 interacts with DNAI2, but not HSP70 or HSP90, distinguishing it from the client/chaperone functions described for other cytoplasmic proteins required for dynein arm assembly such as DNAAF1-4. These data implicate CG31320/HEATR2 in a growing intracellular pre-assembly and transport network that is necessary to deliver functional dynein machinery to the ciliary compartment for integration into the motile axoneme.

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U2 - 10.1371/journal.pgen.1004577

DO - 10.1371/journal.pgen.1004577

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AN - SCOPUS:84907587673

SN - 1553-7390

VL - 10

JO - PLoS Genetics

JF - PLoS Genetics

IS - 9

M1 - e1004577

ER -

HEATR2 Plays a Conserved Role in Assembly of the Ciliary Motile Apparatus

Abstract

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