Cellular sensing by phase separation: Using the process, not just the products

Abstract

Phase separation creates two distinct liquid phases from a single mixed liquid phase, like oil droplets separating from water. Considerable attention has focused on how the products of phase separation-the resulting condensates-might act as biological compartments, bioreactors, filters, and membraneless organelles in cells. Here, we expand this perspective, reviewing recent results showing how cells instead use the process of phase separation to sense intracellular and extracellular changes. We review case studies in phase separation-based sensing and discuss key features, such as extraordinary sensitivity, which make the process of phase separation ideally suited to meet a range of sensory challenges cells encounter.

Keywords: Sup35; biophysics; biosensor; cell biology; cellular regulation; cyclic GMP-AMP synthase; phase separation; phase transition; poly(A)-binding protein; stress response.

Figure 1.

Distinguishing the process and the products of phase separation. A, phase separation of a single-phase solution into dense (droplet) and dilute (surrounding medium) phases. B, mechanisms for forming large fluid structures. This list is not exhaustive. Some mechanisms involve pre-existing phase-separated subunits, whereas others do not involve phase separation at all. C, phase boundaries represent a sharp thermodynamic transition, making them well-suited for sensing small changes in important conditions. D, efficiency and kinetics of large-state changes can differ markedly depending on implementation. Top, synthesis and degradation processes (e.g. by changes in mRNA or protein synthesis and turnover) take minutes to hours and substantial energy expenditure. Bottom, phase separation processes (e.g. phase separation of cGAS upon binding DNA) rearrange matter in place, allowing rapid changes on a system-wide scale in seconds, in many cases spontaneously.

Figure 2.

Proposed functions of phase separation–based sensory systems. The following abbreviations are used: CTD, C-terminal domain; P domain, proline-rich domain; RRM, RNA recognition motif; N, N-terminal prion domain; M, middle domain; DBD, DNA-binding domain; NTase core, nucleotidyltransferase domain.

Figure 3.

Distinct features of the process and the products of phase separation. Both may carry out functions, and specific functions (such as sensing, signal transduction, and isolation of events in time) may rely mainly on features of the process, whereas other specific functions (such as colocalization, filtration, and isolation in space) depend primarily on the products.