Rim4 is a Thermal Sensor and Driver of Meiosis-specific Stress Granules.

Rim4 is a meiosis-specific RNA-binding protein (RBP) that sequesters mRNAs to suppress their translation. Previous work has defined the Rim4 C-terminal low-complexity domain (LCD) as sequences that form self-propagating amyloid-like aggregates. Here, we uncovered a dynamic and reversible form of Rim4 self-assembly primarily triggered by heat during meiosis, proportionally from 30°C to 42°C. The formed thermal Rim4 condensates in cell promptly stimulates stress granule (SG) assembly, recruiting SG-resident proteins, such as Pab1 and Pbp1, and strikingly, decreases the required temperature for meiotic SG formation (∼33°C) by ∼9°C as compared to mitosis (∼42°C). This sensitization of meiotic SG formation to heat effectively prevents meiosis progression and sporulation under harmful thermal turbulence. Meanwhile, the Rim4-positive meiotic SGs protect Rim4 and Rim4-sequestered mRNAs from autophagy to allow a rapid recovery from stalled meiosis upon the stress relief. Mechanistically, we found that the yeast 14-3-3 proteins (Bmh1 and Bmh2) and nucleic acids brake initiation of heat-induced Rim4 self-assembly, and Hsp104 facilitates the restoration of intracellular Rim4 distribution during the recovery.

A ketogenic diet can mitigate SARS-CoV-2 induced systemic reprogramming and inflammation.

The ketogenic diet (KD) has demonstrated benefits in numerous clinical studies and animal models of disease in modulating the immune response and promoting a systemic anti-inflammatory state. Here we investigate the effects of a KD on systemic toxicity in mice following SARS-CoV-2 infection. Our data indicate that under KD, SARS-CoV-2 reduces weight loss with overall improved animal survival. Muted multi-organ transcriptional reprogramming and metabolism rewiring suggest that a KD initiates and mitigates systemic changes induced by the virus. We observed reduced metalloproteases and increased inflammatory homeostatic protein transcription in the heart, with decreased serum pro-inflammatory cytokines (i.e., TNF-α, IL-15, IL-22, G-CSF, M-CSF, MCP-1), metabolic markers of inflammation (i.e., kynurenine/tryptophane ratio), and inflammatory prostaglandins, indicative of reduced systemic inflammation in animals infected under a KD. Taken together, these data suggest that a KD can alter the transcriptional and metabolic response in animals following SARS-CoV-2 infection with improved mice health, reduced inflammation, and restored amino acid, nucleotide, lipid, and energy currency metabolism.