Summary Several large-scale genome-wide association studies genetically linked IRGM to Crohn’s disease and other inflammatory disorders in which the IRGM appears to have a protective function. However, the mechanism by which IRGM accomplishes this anti-inflammatory role remains unclear. Here, we reveal that IRGM/Irgm1 is a negative regulator of the NLRP3 inflammasome activation. We show that IRGM expression, which is increased by PAMPs, DAMPs, and microbes, can suppress the pro-inflammatory responses provoked by the same stimuli. IRGM/Irgm1 negatively regulates IL-1β maturation by suppressing the activation of the NLRP3 inflammasome. Mechanistically, we show that IRGM interacts with NLRP3 and ASC and hinders inflammasome assembly by blocking their oligomerization. Further, IRGM mediates selective autophagic degradation of NLRP3 and ASC. By suppressing inflammasome activation, IRGM/Irgm1 protects from pyroptosis and gut inflammation in a Crohn’s disease experimental mouse model. This study for the first time identifies the mechanism by which IRGM is protective against inflammatory disorders.

Yin Yang 1 (YY1), a dual function transcription factor, is known to regulate transcriptional activation and repression of many genes associated with multiple cellular processes including cellular differentiation, DNA repair, autophagy, cell survival vs. apoptosis, and cell division. Owing to its role in processes that upon deregulation are linked to malignant transformation, YY1 has been implicated as a major driver of many cancers. While a large body of evidence supports the role of YY1 as a tumor promoter, recent reports indicated that YY1 also functions as a tumor suppressor. The mechanism by which YY1 brings out opposing outcome in tumor growth vs. suppression is not completely clear and some of the recent reports have provided significant insight into this. Likewise, the mechanism by which YY1 functions both as a transcriptional activator and repressor is not completely clear. It is likely that the proteins with which YY1 interacts might determine its function as an activator or repressor of transcription as well as its role as a tumor suppressor or promoter. Hence, a collection of YY1-protein interactions in the context of different cancers would help us gain an insight into how YY1 promotes or suppresses cancers. This review focuses on the YY1 interacting partners and its target genes in different cancer models. Finally, we discuss the possibility of therapeutically targeting the YY1 in cancers where it functions as a tumor promoter.

Sequestration of protein aggregates in inclusion bodies and their subsequent degradation prevents proteostasis imbalance, cytotoxicity, and proteinopathies. The underlying molecular mechanisms controlling the turnover of protein aggregates are mostly uncharacterized. Herein, we show that a TRIM family protein, TRIM16, governs the process of stress‐induced biogenesis and degradation of protein aggregates. TRIM16 facilitates protein aggregate formation by positively regulating the p62‐NRF2 axis. We show that TRIM16 is an integral part of the p62‐KEAP1‐NRF2 complex and utilizes multiple mechanisms for stabilizing NRF2. Under oxidative and proteotoxic stress conditions, TRIM16 activates ubiquitin pathway genes and p62 via NRF2, leading to ubiquitination of misfolded proteins and formation of protein aggregates. We further show that TRIM16 acts as a scaffold protein and, by interacting with p62, ULK1, ATG16L1, and LC3B, facilitates autophagic degradation of protein aggregates. Thus, TRIM16 streamlines the process of stress‐induced aggregate clearance and protects cells against oxidative/proteotoxic stress‐induced toxicity in vitro and in vivo. Taken together, this work identifies a new mechanism of protein aggregate turnover, which could be relevant in protein aggregation‐associated diseases such as neurodegeneration.

Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid‐sensing pathways leading to interferon‐stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG‐I, and mediates their p62‐dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS‐STING and RIG‐I‐MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases.

(2019) TRIM16 governs the biogenesis and disposal of stressinduced protein aggregates to evade cytotoxicity: implication for neurodegeneration and cancer,