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Membrane-Embedded RNF26 Binds Perinuclear Vimentin Filaments to Integrate ER and Endolysosomal Responses to Proteotoxic Stress
Tom Cremer 1, 2, Lenard M. Voortman 1, Erik Bos 1, 2, Marlieke L.M. Jongsma 1, 2, Laurens R. ter Haar 1, Cami M.P. Talavera Ormeño 1, Ruud H.M. Wijdeven 1, 2, 3, Robbert Q. Kim 1, George M.C. Janssen 1, Peter A. van Veelen 1, Roman I. Koning 1, Jacques Neefjes1, 2, * and Ilana Berlin1, 2, *.1 Department of Cell and Chemical Biology, 2 Oncode Institute, Leiden University Medical Center LUMC, Leiden NL
Background: Compartmentalization of organelles in space and time affects their functional state and enables higher order regulation of essential cellular processes. In times of stress, the cell’s most expansive organelle – the ER – remodels its perinuclear subdomain into an ER quality control compartment (ERQC), where segregation and clearance of misfolded proteins take place. Then, during the recovery phase, the ERQC self-destructs through feeding of its membranes directly into the proteolytic endolysosomes. Yet, what guards the perinuclear ER identity and drives formation and disposal of the ERQC remains unclear.
Aim: Identify the perinuclear anchor for the ER and endolysosomes and resolve the relevant molecular mechanism.
Results:In this study, we identify Vimentin intermediate filaments as critical perinuclear anchors for the ER and endolysosomes. We show that Vimentin collaborates with the ER-embedded ubiquitin ligase ring finger protein 26 (RNF26) to promote maintenance of the perinuclear ER subdomain and its associated endolysosomal cloud. We find that Vimentin filaments preferentially engage RNF26 in a catalytically inactive state through a direct interaction with the C-terminus of its atypical RING domain. Because the Vimentin cytoskeleton predominates near the nucleus of the cell, its binding restricts RNF26 within the perinuclear ER subdomain. Activation of RNF26 ligase function in turn mediates positioning of endolysosomes in perinuclear space through the formation of ER membrane contact sites (ER MCS). The resulting juxtaposition of biosynthetic and proteolytic compartments facilitates recovery from ER stress via the Sec62-mediated ERphagy pathway in a manner dependent on both RNF26 and Vimentin.
Conclusions:Taken together, our findings intimate a dynamic interplay between Vimentin and RNF26, which regulates organellar distribution in steady state and drives acute perinuclear coalescence of the ERQC with endolysosomes in response to proteotoxic stress. Our study thus reveals a new scaffolding mechanism underpinning spatiotemporal integration of organelles, with implications for proteostasis.
(This work was supported by an ERC Adv grant (ERCOPE) to Jacques Neefjes.)
Speakers
Ilana Berlin