Competing Protein-RNA Interaction Networks Control Multiphase Intracellular Organization

David W. Sanders, Nancy Kedersha, Daniel S.W. Lee, Amy R. Strom, Victoria Drake, Joshua A. Riback, Dan Bracha, Jorine M. Eeftens, Allana Iwanicki, Alicia Wang, Ming Tzo Wei, Gena Whitney, Shawn M. Lyons, Paul Anderson, William M. Jacobs, Pavel Ivanov, Clifford P. Brangwynne

Research output: Contribution to journalArticle

9 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)306-324.e28
JournalCell
Volume181
Issue number2
DOIs
StatePublished - Apr 16 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Keywords

  • condensates
  • G3BP
  • membraneless organelles
  • multiphase
  • P-bodies
  • phase separation
  • RNA binding
  • stress granules
  • UBAP2L
  • USP10

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  • Cite this

    Sanders, D. W., Kedersha, N., Lee, D. S. W., Strom, A. R., Drake, V., Riback, J. A., Bracha, D., Eeftens, J. M., Iwanicki, A., Wang, A., Wei, M. T., Whitney, G., Lyons, S. M., Anderson, P., Jacobs, W. M., Ivanov, P., & Brangwynne, C. P. (2020). Competing Protein-RNA Interaction Networks Control Multiphase Intracellular Organization. Cell, 181(2), 306-324.e28. https://doi.org/10.1016/j.cell.2020.03.050