Activation of the amino acid starvation response (AAR) increases lifespan and acute stress resistance as well as regulates inflammation. However, the underlying mechanisms remain unclear. Here, we show that activation of AAR pharmacologically by Halofuginone (HF) significantly inhibits production of the proinflammatory cytokine interleukin 1β (IL-1β) and provides protection from intestinal inflammation in mice. HF inhibits IL-1β through general control nonderepressible 2 kinase (GCN2)–dependent activation of the cytoprotective integrated stress response (ISR) pathway, resulting in rerouting of IL-1β mRNA from translationally active polysomes to inactive ribocluster complexes—such as stress granules (SGs)—via recruitment of RNA-binding proteins (RBPs) T cell–restricted intracellular antigen-1(TIA-1)/TIA-1–related (TIAR), which are further cleared through induction of autophagy. GCN2 ablation resulted in reduced autophagy and SG formation, which is inversely correlated with IL-1β production. Furthermore, HF diminishes inflammasome activation through suppression of reactive oxygen species (ROS) production. Our study unveils a novel mechanism by which IL-1β is regulated by AAR and further suggests that administration of HF might offer an effective therapeutic intervention against inflammatory diseases. Reduced intake of food (also known as dietary restriction) without malnutrition has been shown to benefit health in humans and animals, including an increase in life expectancy, metabolic fitness, and resistance to acute stress. Recent studies have attributed the benefits associated with dietary restriction to the reduced intake of amino acids. However, the underlying mechanisms through which amino acid restriction regulates various homeostatic processes are poorly defined. Here, we show that activation of amino acid starvation response (AAR) by the small molecule Halofuginone (HF) results in a significant inhibition of production of interleukin 1β (IL-1β), a proinflammatory mediator. We find that AAR provides protection from intestinal inflammation–associated pathology in a mouse model of colitis through a novel mechanism involving the formation of riboclusters (groups of RNA-binding proteins (RBPs) and stalled mRNA complexes) and autophagy. We further show that HF-mediated inhibition in IL-1β production is dependent on general control nonderepressible 2 kinase (GCN2), an amino acid deprivation sensor. This study provides the mechanisms regulating AAR-induced benefits in the context of inflammation and further suggests that the administration of HF might offer an effective therapeutic intervention against inflammatory diseases in mammals.

Cancer immunotherapy has become an indispensable mode of treatment for a multitude of solid tumor cancers. Colorectal cancer (CRC) has been one of the many cancer types to benefit from immunotherapy, especially in advanced disease where standard treatment fails to prevent recurrence or results in poor survival. The efficacy of immunotherapy in CRC has not been without challenge, as early clinical trials observed dismal responses in unselected CRC patients treated with checkpoint inhibitors. Many studies and clinical trials have since refined immunotherapies available for CRC, solidifying immunotherapy as a powerful asset for CRC treatment. This review article examines CRC immunotherapies, from their foundation, through emerging avenues for improvement, to future directions.

Proper cell division relies on the coordinated regulation between a structural component, the mitotic spindle, and a regulatory component, anaphase-promoting complex/cyclosome (APC/C). Hematopoietic PBX-interacting protein (HPIP) is a microtubule-associated protein that plays a pivotal role in cell proliferation, cell migration, and tumor metastasis. Here, using HEK293T and HeLa cells, along with immunoprecipitation and immunoblotting, live-cell imaging, and protein-stability assays, we report that HPIP expression oscillates throughout the cell cycle and that its depletion delays cell division. We noted that by utilizing its D box and IR domain, HPIP plays a dual role both as a substrate and inhibitor, respectively, of the APC/C complex. We observed that HPIP enhances the G₂/M transition of the cell cycle by transiently stabilizing cyclin B1 by preventing APC/C–Cdc20–mediated degradation, thereby ensuring timely mitotic entry. We also uncovered that HPIP associates with the mitotic spindle and that its depletion leads to the formation of multiple mitotic spindles and chromosomal abnormalities, results in defects in cytokinesis, and delays mitotic exit. Our findings uncover HPIP as both a substrate and an inhibitor of APC/C–Cdc20 that maintains the temporal stability of cyclin B1 during the G₂/M transition and thereby controls mitosis and cell division.