Ciliary dynein motor preassembly is regulated by Wdr92 in association with HSP90 co-chaperone, R2TP.

Petra Zur Lage,Panagiota Stefanopoulou,Andrew P Jarman,Niall Quinn,Katarzyna Styczynska-Soczka,Alex Von Kriegsheim,Girish Mali,Pleasantine Mill

doi:10.1083/jcb.201709026

Abstract

The massive dynein motor complexes that drive ciliary and flagellar motility require cytoplasmic preassembly, a process requiring dedicated dynein assembly factors (DNAAFs). How DNAAFs interact with molecular chaperones to control dynein assembly is not clear. By analogy with the well-known multifunctional HSP90-associated cochaperone, R2TP, several DNAAFs have been suggested to perform novel R2TP-like functions. However, the involvement of R2TP itself (canonical R2TP) in dynein assembly remains unclear. Here we show that in Drosophila melanogaster, the R2TP-associated factor, Wdr92, is required exclusively for axonemal dynein assembly, likely in association with canonical R2TP. Proteomic analyses suggest that in addition to being a regulator of R2TP chaperoning activity, Wdr92 works with the DNAAF Spag1 at a distinct stage in dynein preassembly. Wdr92/R2TP function is likely distinct from that of the DNAAFs proposed to form dynein-specific R2TP-like complexes. Our findings thus establish a connection between dynein assembly and a core multifunctional cochaperone.

Highlights

Many tasks within the cell are accomplished by highly organized multicomponent protein complexes, the biogenesis of which requires guided assembly by molecular chaperones (Makhnevych and Houry, 2012)
We show that Wdr92 protein is associated with both dynein heavy chains (HCs) and intermediate chains (ICs), and propose that it acts as a specificity factor to bring partially assembled dynein clients to R2TP/HSP90 at a late stage of cytoplasmic assembly
WDR92’s proteomic association with the HSP90 cochaperone, R2TP, has been known for some time, very little was known of the function of WDR92 or the significance of this association in vivo (Sardiu et al, 2008; Boulon et al, 2010; Choi et al, 2011; Glatter et al, 2011)

Summary

Introduction

Many tasks within the cell are accomplished by highly organized multicomponent protein complexes, the biogenesis of which requires guided assembly by molecular chaperones (Makhnevych and Houry, 2012). A group of some 10 proteins have been identified that facilitate this assembly pathway—collectively known as axonemal dynein assembly factors (DNAAFs; Mitchison et al, 2012) Several of these proteins were discovered through identifying causative mutations in human primary ciliary dyskinesia (PCD), characterized by ciliary/flagellar immotility (Omran et al, 2008; Mitchison et al, 2012; Knowles et al, 2013; Moore et al, 2013; Tarkar et al, 2013; Zariwala et al, 2013; Diggle et al, 2014). Aside from PCD, protein homeostasis is increasingly associated with diseases from neurodegeneration to cancer, and is a promising target for therapeutic intervention (Lindquist and Kelly, 2011)

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Conclusion