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Stress Dependent Condensate Formation Regulated by the Ubiquitin Related Modifier Urm1

ABSTRACT: The ability of proteins and RNA to coalesce into phase-separated assemblies is an emergent principle in organizing membraneless cellular compartments such as stress granules (SGs) and the nucleolus. While the individual constituents of these compartments have become increasingly well documented, the mechanisms underlying their rapid and reversible formation are only partially understood. Here, we report that the ubiquitin related modifier Urm1 functions in promoting the assembly of phase-separated compartments in yeast. Through its intrinsic ability to self-associate and interact with target proteins in a pH-sensitive manner, stress-induced Urm1 conjugation, mediated by the E1-like enzyme Uba4, drives efficient deposition of target proteins into phase-separated assemblies, including SGs and the nucleolus. Yeast cells lacking urmylation exhibit condensate assembly defects, causing reduced fitness upon exposure to stress-induced challenges. We propose that Urm1 acts as a reversible molecular “adhesive” to drive condensate formation of a wide range of proteins under various stress conditions.

INSTRUMENT(S): Q Exactive HF, Orbitrap Exploris 240

ORGANISM(S): Saccharomyces Cerevisiae (baker's Yeast)

SUBMITTER: Lucas Cairo

LAB HEAD: F., Ulrich, Hartl

PROVIDER: PXD044486 | Pride | 2024-06-28

REPOSITORIES: Pride

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			Action	DRS
	20190327_coreQEP2_AnWe_LC10-95_SA_Orbi3150Sample01.raw	Raw
	20190327_coreQEP2_AnWe_LC10-95_SA_Orbi3150Sample02.raw	Raw
	20190327_coreQEP2_AnWe_LC10-95_SA_Orbi3150Sample03.raw	Raw
	20190327_coreQEP2_AnWe_LC10-95_SA_Orbi3150Sample04.raw	Raw
	20190327_coreQEP2_AnWe_LC10-95_SA_Orbi3150Sample05.raw	Raw

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Project description:The cellular stress response plays a vital role in regulating homeostasis by modulating cell survival and death. Stress granules (referred to as SGs) are cytoplasmic compartments that allow cells to survive various stressors. Defects in SG assembly and disassembly have been found to play important roles in neurodegenerative diseases, antiviral responses and cancer1–5. Inflammasomes are multi-protein heteromeric complexes that sense intracellular pathogen- and damage-associated molecular patterns and assemble into cytosolic compartments called ASC specks to facilitate caspase-1 (CASP1) activation. This activation of inflammasomes induces secretion of the leaderless proinflammatory cytokines IL-1β and IL-18 and also drives cell fate towards pyroptosis, a form of programmed inflammatory cell death that plays major role in health and disease6–12. Cellular stress sensing can trigger both SGs and inflammasomes; however, they drive contrasting cell fate decisions during stress conditions. Crosstalk between SGs and inflammasomes to decide cell fate has not been well studied. Here we show that the induction of SGs specifically inhibits NLRP3 inflammasome activation, ASC speck formation and pyroptosis. The SG protein DDX3X interacts with NLRP3 to drive inflammasome activation in the absence of SGs. Assembly of SGs leads to the sequestration of DDX3X to inhibit NLRP3 inflammasome function. SGs and the NLRP3 inflammasome compete for DDX3X molecules to coordinate the activation of innate responses and subsequent cell fate decisions under stress conditions. Induction of SGs or loss of DDX3X in the myeloid compartment leads to decreased production of inflammasome-dependent cytokines in vivo. Our findings suggest that macrophages utilize DDX3X availability to interpret stress signals and choose between pro-survival SGs and pyroptotic ASC specks. Together, our data show the role of DDX3X in driving NLRP3 inflammasome and SG assembly, informing a new rheostat-like mechanistic paradigm for regulating live or die cell fate decisions under stress conditions.

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Stress Dependent Condensate Formation Regulated by the Ubiquitin Related Modifier Urm1

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