Glucocorticoid receptor (GR) exerts anti-inflammatory action in part by antagonizing proinflammatory transcription factors such as the nuclear factor kappa-b (NFKB). Here, we assess the crosstalk of activated GR and RELA (p65, major NFKB component) by global identification of their binding sites and target genes. We show that coactivation of GR and p65 alters the repertoire of regulated genes and results in their association with novel sites in a mutually dependent manner. These novel sites predominantly cluster with p65 target genes that are antagonized by activated GR and vice versa. Our data show that coactivation of GR and NFKB alters signaling pathways that are regulated by each factor separately and provide insight into the networks underlying the GR and NFKB crosstalk.

Comparative expression profiling was shown to be a highly efficient method in identifying deregulated genes and pathways. Moreover, tissue microarrays and computerized image analysis allowed for the high-throughput and unbiased assessment of histopathologic sections, adding substantial confidence in pathologic evaluations. More importantly, our results suggest an early primary role of HIF-1 in alveolar epithelial cell homeostasis and disease pathogenesis, provide insights on the pathophysiologic differences of different interstitial pneumonias, and indicate the importance of assessing the efficacy of pharmacologic inhibitors of HIF-1 activity in the treatment of pulmonary fibrosis.

Dietary restriction (DR) was shown to impact on tumor growth with very variable effects depending on the cancer type. However, how DR limits cancer progression remains largely unknown. Here, we demonstrate that feeding mice a low-protein (Low PROT) isocaloric diet but not a low-carbohydrate (Low CHO) diet reduced tumor growth in three independent mouse cancer models. Surprisingly, this effect relies on anticancer immunosurveillance, as depleting CD8 T cells, antigen-presenting cells (APCs), or using immunodeficient mice prevented the beneficial effect of the diet. Mechanistically, we established that a Low PROT diet induces the unfolded protein response (UPR) in tumor cells through the activation of IRE1α and RIG1 signaling, thereby resulting in cytokine production and mounting an efficient anticancer immune response. Collectively, our data suggest that a Low PROT diet induces an IRE1α-dependent UPR in cancer cells, enhancing a CD8-mediated T cell response against tumors.

Similar to other RNA viruses, SARS-CoV-2 must (1) enter a target/host cell, (2) reprogram it to ensure its replication, (3) exit the host cell, and (4) repeat this cycle for exponential growth. During the exit step, the virus hijacks the sophisticated machineries that host cells employ to correctly fold, assemble, and transport proteins along the exocytic pathway. Therefore, secretory pathway–mediated assemblage and excretion of infective particles represent appealing targets to reduce the efficacy of virus biogenesis, if not to block it completely. Here, we analyze and discuss the contribution of the molecular machines operating in the early secretory pathway in the biogenesis of SARS-CoV-2 and their relevance for potential antiviral targeting. The fact that these molecular machines are conserved throughout evolution, together with the redundancy and tissue specificity of their components, provides opportunities in the search for unique proteins essential for SARS-CoV-2 biology that could also be targeted with therapeutic objectives. Finally, we provide an overview of recent evidence implicating proteins of the early secretory pathway as potential antiviral targets with effective therapeutic applications.

Anterior gradient 2 ( AGR 2) is a dimeric protein disulfide isomerase family member involved in the regulation of protein quality control in the endoplasmic reticulum ( ER ). Mouse AGR 2 deletion increases intestinal inflammation and promotes the development of inflammatory bowel disease ( IBD ). Although these biological effects are well established, the underlying molecular mechanisms of AGR 2 function toward inflammation remain poorly defined. Here, using a protein–protein interaction screen to identify cellular regulators of AGR 2 dimerization, we unveiled specific enhancers, including TMED 2, and inhibitors of AGR 2 dimerization, that control AGR 2 functions. We demonstrate that modulation of AGR 2 dimer formation, whether enhancing or inhibiting the process, yields pro‐inflammatory phenotypes, through either autophagy‐dependent processes or secretion of AGR 2, respectively. We also demonstrate that in IBD and specifically in Crohn's disease, the levels of AGR 2 dimerization modulators are selectively deregulated, and this correlates with severity of disease. Our study demonstrates that AGR 2 dimers act as sensors of ER homeostasis which are disrupted upon ER stress and promote the secretion of AGR 2 monomers. The latter might represent systemic alarm signals for pro‐inflammatory responses.