@article{0d546b438bab4f54864740501851685b,
title = "Competing Protein-RNA Interaction Networks Control Multiphase Intracellular Organization",
abstract = "Liquid-liquid phase separation (LLPS) mediates formation of membraneless condensates such as those associated with RNA processing, but the rules that dictate their assembly, substructure, and coexistence with other liquid-like compartments remain elusive. Here, we address the biophysical mechanism of this multiphase organization using quantitative reconstitution of cytoplasmic stress granules (SGs) with attached P-bodies in human cells. Protein-interaction networks can be viewed as interconnected complexes (nodes) of RNA-binding domains (RBDs), whose integrated RNA-binding capacity determines whether LLPS occurs upon RNA influx. Surprisingly, both RBD-RNA specificity and disordered segments of key proteins are non-essential, but modulate multiphase condensation. Instead, stoichiometry-dependent competition between protein networks for connecting nodes determines SG and P-body composition and miscibility, while competitive binding of unconnected proteins disengages networks and prevents LLPS. Inspired by patchy colloid theory, we propose a general framework by which competing networks give rise to compositionally specific and tunable condensates, while relative linkage between nodes underlies multiphase organization.",
keywords = "G3BP, P-bodies, RNA binding, UBAP2L, USP10, condensates, membraneless organelles, multiphase, phase separation, stress granules",
author = "Sanders, {David W.} and Nancy Kedersha and Lee, {Daniel S.W.} and Strom, {Amy R.} and Victoria Drake and Riback, {Joshua A.} and Dan Bracha and Eeftens, {Jorine M.} and Allana Iwanicki and Alicia Wang and Wei, {Ming Tzo} and Gena Whitney and Lyons, {Shawn M.} and Paul Anderson and Jacobs, {William M.} and Pavel Ivanov and Brangwynne, {Clifford P.}",
note = "Funding Information: We thank Rivkah Brown, Chang-Hyun Choi, Evangelos Gatzogiannis, Brittany Grego, Anastasia Repouliou, and Claire Riggs for assistance with experiments, and all Brangwynne Lab members for helpful critiques. We thank J. Paul Taylor (St. Jude Children's Hospital) and Simon Alberti (CMCB/BIOTEC) for discussing independently collected, corroborating data. This work was supported by the Howard Hughes Medical Institute, the St. Jude Research Collaborative on Membrane-less Organelles, the NIH (U01 DA040601), and an NSF CAREER award (125035) (C.P.B.). D.W.S. acknowledges support through the NIH (F32 GM130072); D.S.W.L. NSF Graduate Research Fellowship Program (DCE-1656466); A.R.S. LSRF Fellowship from Mark Foundation For Cancer Research; D.B. Cross-Disciplinary Postdoctoral Fellowship from Human Frontiers Science Program; J.M.E. NWO Rubicon Fellowship; N.K. S.M.L. and P.A. NIH (R35 GM126901); S.M.L. NIH (K99 GM124458); and P.I. NIH (R01 GM126150). Conceptualization: D.W.S. and C.P.B.; Methodology: D.W.S. N.K. D.S.W.L. V.D. D.B. J.A.R. A.I. M.-T.W. and W.M.J.; Software: D.S.W.L. and W.M.J.; Formal Analysis, D.W.S. N.K. D.S.W.L. J.A.R. D.B. A.W. and W.M.J.; Investigation: D.W.S. N.K. A.R.S. V.D. J.A.R. A.I. A.W. M.-T.W. G.W. and S.M.L.; Resources: D.W.S. N.K. D.S.W.L. A.R.S. V.D. D.B. J.M.E. A.W. and S.M.L.; Writing ? Original Draft: D.W.S. and C.P.B.; Writing ? Review & Editing: D.W.S. N.K. A.R.S. W.M.J. and C.P.B.; Visualization: D.W.S. A.R.S. and W.M.J.; Supervision and Funding Acquisition, P.A. P.I. and C.P.B. Patent applications have been filed based on this work. Funding Information: We thank Rivkah Brown, Chang-Hyun Choi, Evangelos Gatzogiannis, Brittany Grego, Anastasia Repouliou, and Claire Riggs for assistance with experiments, and all Brangwynne Lab members for helpful critiques. We thank J. Paul Taylor (St. Jude Children{\textquoteright}s Hospital) and Simon Alberti (CMCB/BIOTEC) for discussing independently collected, corroborating data. This work was supported by the Howard Hughes Medical Institute , the St. Jude Research Collaborative on Membrane-less Organelles , the NIH ( U01 DA040601 ), and an NSF CAREER award ( 125035 ) (C.P.B.). D.W.S. acknowledges support through the NIH ( F32 GM130072 ); D.S.W.L., NSF Graduate Research Fellowship Program ( DCE-1656466 ); A.R.S., LSRF Fellowship from Mark Foundation For Cancer Research ; D.B., Cross-Disciplinary Postdoctoral Fellowship from Human Frontiers Science Program ; J.M.E., NWO Rubicon Fellowship; N.K., S.M.L., and P.A., NIH ( R35 GM126901 ); S.M.L., NIH ( K99 GM124458 ); and P.I., NIH ( R01 GM126150 ). Publisher Copyright: {\textcopyright} 2020 Elsevier Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2020",
month = apr,
day = "16",
doi = "10.1016/j.cell.2020.03.050",
language = "English (US)",
volume = "181",
pages = "306--324.e28",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "2",
}