Stress granules display bistable dynamics modulated by Cdk

Abstract

Stress granules are conserved biomolecular condensates that originate in response to many stress conditions. These membraneless organelles contain nontranslating mRNAs and a diverse subproteome, but our knowledge on their regulation and functional relevance is still incipient.Here we describe a mutual-inhibition interplay between stress granules and Cdc28, the budding yeast Cdk. Amongst Cdc28 interactors acting as negative modulators of Start we have identified Whi8, an RNA-binding protein that localizes to SGs and recruits the mRNA of CLN3, the most upstream G1 cyclin, for efficient translation inhibition and Cdk inactivation under stress. However, Whi8 also contributes to recruiting Cdc28 to SGs, where it acts to promote their dissolution. As predicted by a mutual-inhibition framework, the SG constitutes a bistable system that is modulated by Cdk. Since mammalian cells display a homologous mechanism, we propose that the opposing functions of specific mRNA-binding proteins and Cdks subjugate SG dynamics to a conserved hysteretic switch.

Single-embryo phosphoproteomics reveals the importance of intrinsic disorder in cell cycle dynamics

“…Since CDK sites tend to cluster together in IDRs (Holt et al, 2009;Moses et al, 2007), and our data shows that many cell cycle-regulated CDK substrates are key components of MLOs, it is likely that CDK-mediated phosphorylation will affect MLO structure. Indeed, CDKs can control formation of stress granules (Yahya et al, 2021) and histone bodies (Hur et al, 2020), and possibly other MLOs. An emerging model is that liquid-liquid phase separation, which depends on weak interactions between IDRs, underlies the self-assembly of many MLOs (Banani et al, 2017;Hyman et al, 2014;Woodruff et al, 2018).…”

“…Thus, MLO assembly and disassembly occurs in a cell cycle-dependent manner. MLOs are thought to assemble by mechanisms involving multivalent interactions between intrinsically-disordered regions (IDR) of proteins (Banani et al, 2017), and this process can be regulated by protein kinases, including CDKs (Berchtold et al, 2018;Hur et al, 2020;Rai et al, 2018;Yahya et al, 2021). Protein phosphorylation in general is enriched in IDRs (Iakoucheva et al, 2004) and this also appears to be true for CDKs (Holt et al, 2009;Michowski et al, 2020;Moses et al, 2007).…”

Heat stress reveals the existence of a specialized variant of the pachytene checkpoint in meiosis of Arabidopsis thaliana

“…It has been previously hypothesized that the presence of CDKA;1 in SGs would allow a cell to resume cell division activity in Arabidopsis after attenuation of the stress (Kosmacz et al, 2019). CDKs typically require a co-factor, called cyclin, for their activity and in budding yeast, WHI8, an RNA-binding protein, was shown to bind to and recruit the mRNA of the cyclin CLN3 to SGs upon heat stress causing the inhibition of CLN3 translation (Yahya et al, 2021). Interestingly, CDC28, the homolog of CDKA;1 in budding yeast, itself is also recruited to SGs by WHI8 and has been found to play an important role in SG dissolution and the translation of SG-recruited mRNAs, such as the one of CLN3, upon release from stress.…”