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Ubiquitin Modulates Liquid-Liquid Phase Separation of UBQLN2 via Disruption of Multivalent Interactions

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Dao, Thuy P., Kolaitis, Regina-Maria, Kim, Hong Joo, O’Donovan, Kevin, Martyniak, Brian, Colicino, Erica, Hehnly, Heidi, Taylor, J. Paul, Castañeda, Carlos A.·2018·Molecular Cell
DOI 10.1016/j.molcel.2018.02.004
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Abstract

Summary Under stress, certain eukaryotic proteins and RNA assemble to form membraneless organelles known as stress granules. The most well-studied stress granule components are RNA-binding proteins that undergo liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by intrinsically-disordered low-complexity domains (LCDs). Here we show that stress granules include proteasomal shuttle factor UBQLN2, a LCD-containing protein structurally and functionally distinct from RNA-binding proteins. In vitro, UBQLN2 exhibits LLPS at physiological conditions. Deletion studies correlate oligomerization with UBQLN2’s ability to phase separate and form stress-induced cytoplasmic puncta in cells. Using NMR spectroscopy, we mapped weak, multivalent interactions that promote UBQLN2 oligomerization and LLPS. Ubiquitin or polyubiquitin binding, obligatory for UBQLN2’s biological functions, eliminates UBQLN2 LLPS, thus serving as a “switch” between droplet and disperse phases. We postulate that UBQLN2 LLPS enables its recruitment to stress granules where its interactions with ubiquitinated substrates reverse LLPS to enable shuttling of clients out of stress granules.

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Metadata

Authors
Dao, T. P., Kolaitis, R.-M., Kim, H. J., O’Donovan, K., Martyniak, B., Colicino, E., Hehnly, H., Taylor, J. P., & Castañeda, C. A.
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2018-03
Volume
69
Issue
6
Pages
965-978.e6
ISSN
1097-2765 (ISSN-L)
DOI
10.1016/j.molcel.2018.02.004
OpenAlex
W2790286335
Cited by
341
References
8
FWCI
10.83
Type
journal article
Language
en
Open access
bronze
Licence
Funders
  • ALS Association (17-IIP-369, 18-IIP-400, 16-IIP-270, 18-IIA-419)
  • Syracuse University
  • NIH (R00 GM107355, R35NS097974, 1S10OD012254)
  • DOD (PC160083)
  • Carol Baldwin Foundation for Central New York
  • The Packard Center for ALS Research at the Johns Hopkins University (2002289810)
  • Clinical Research in ALS (5U65NS092091-04)
  • American-Lebanese-Syrian Associated Charities
  • Howard Hughes Medical Institute (045104)
  • Target ALS (19[PG004827])

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