Amyloid Beta oligomers prevents Lysosomal targeting of miRNP to stop its recycling and target repression in glial cells

On exposure to Amyloid Beta Oligomers (Aβ1-42), glial cells start expressing proinflammatory cytokines although there has been increase in repressive miRNAs levels as well. Exploring the mechanism of this potential immunity of target cytokine mRNAs against repressive miRNAs in amyloid beta exposed glial cells, we have identified differential compartmentalization of repressive miRNAs in glial cells to explain this aberrant miRNA function. While the target mRNAs were found to be associated with polysomes attached to endoplasmic reticulum, the miRNPs found to be present predominantly with endosomes that failed to recycle to endoplasmic reticulum attached polysomes to repress mRNA targets in Aβ1-42 treated cells. Aβ1-42 oligomers, by masking the Rab7 proteins on endosomal surface, affects Rab7 interaction with Rab Interacting Lysosomal Protein (RILP) to restrict lysosomal targeting and recycling of miRNPs. RNA processing body or P-body localization of the miRNPs also get enhanced in amyloid beta treated cells as a consequence of enhanced endosomal retention of miRNPs. Interestingly, depletion of P-body components partly rescues the miRNA function in glial cells exposed to amyloid beta and restricts the excess cytokine expression there.

Multifunctional RNase MCPIP1 and its Role in Cardiovascular Diseases

: Monocyte chemoattractant protein-1 induced protein 1 (MCPIP1), one of the MCPIP family members, is characterized by the presence of both C-x8-C-x5-C-x3-H (CCCH)-type zinc finger and PilT-N-terminal domains. As a potent regulator of innate immunity, MCPIP1 exerts anti-inflammatory effects through its ribonuclease (RNase) and deubiquitinating enzyme activities to degrade cytokine mRNAs and inhibit nuclear factor-kappa B (NF-κB), respectively. MCPIP1 is expressed not only in immune cells but also in many other cell types, including cardiomyocytes, vascular endothelial cells (ECs) and smooth muscle cells (SMCs). Increasing evidence indicates that MCPIP1 plays a role in the regulation of cardiac functions and is involved in the processes of vascular diseases, such as ischemia-reperfusion (I/R) and atherosclerosis. To better understand the emerging roles of MCPIP1 in the cardiovascular system, we reviewed the current literature with respect to MCPIP1 functions and discussed its association with the pathogenesis of cardiovascular diseases and the implication as a therapeutic target.

Human coronaviruses disassemble processing bodies

The Coronaviridae are a family of viruses with large RNA genomes. Seven coronaviruses (CoVs) have been shown to infect humans, including the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease of 2019 (COVID-19). The host response to CoV infection is complex and regulated, in part, by intracellular antiviral signaling pathways triggered in the first cells that are infected. Emerging evidence suggests that CoVs hijack these antiviral responses to reshape the production of interferons and proinflammatory cytokines. Processing bodies (PBs) are membraneless ribonucleoprotein granules that mediate decay or translational suppression of cellular mRNAs; this is particularly relevant for proinflammatory cytokine mRNA which normally reside in PBs and are repressed. Emerging evidence also suggests that PBs or their components play important direct-acting antiviral roles, providing a compelling reason for their frequent disassembly by many viruses. No information is known about how human CoVs impact PBs. Here, we provide data to show that infection with the human CoV, OC43, causes PB disassembly. Moreover, we show that several SARS-CoV-2 gene products also mediate PB loss and virus-induced PB loss correlates with elevated levels of proinflammatory cytokine mRNAs that would normally be repressed in PBs. Finally, we demonstrate that stimulating PB formation prior to OC43 infection restricts viral replication. These data suggest that SARS-CoV-2 and other CoVs disassemble PBs during infection to support viral replication and evade innate immune responses. As an unintended side effect, the disassembly of PBs enhances translation of proinflammatory cytokine mRNAs which normally reside in PBs, thereby reshaping the subsequent immune response.

The Trans-omics Landscape of COVID-19

System-wide molecular characteristics of COVID-19, especially in those patients without comorbidities, have not been fully investigated. We compared extensive molecular profiles of blood samples from 231 COVID-19 patients, ranging from asymptomatic to critically ill, importantly excluding those with any comorbidities. Amongst the major findings, asymptomatic patients were characterized by highly activated anti-virus interferon, T/natural killer (NK) cell activation, and transcriptional upregulation of inflammatory cytokine mRNAs. However, given very abundant RNA binding proteins (RBPs), these cytokine mRNAs could be effectively destabilized hence preserving normal cytokine levels. In contrast, in critically ill patients, cytokine storm due to RBPs inhibition and tryptophan metabolites accumulation contributed to T/NK cell dysfunction. A machine-learning model was constructed which accurately stratified the COVID-19 severities based on their multi-omics features. Overall, our analysis provides insights into COVID-19 pathogenesis and identifies targets for intervening in treatment.

Gossypol but Not Cottonseed Extracts or Lipopolysaccharides Stimulates HuR Gene Expression in Mouse Macrophages (P06-071-19)

Objectives Human antigen R (HuR) is a homolog of Drosophila embryonic lethal abnormal vision (ELAV1). HuR binds to, stabilizes cytokine mRNAs, and plays an important role in tumorigenesis and inflammation. Plant extracts and compounds that can regulate HuR gene expression may have nutritional and therapeutic value, but no prior research was done. The objective of this study was to evaluate the effect of cottonseed extracts, anti-nutritional gossypol and endotoxin lipopolysaccharides (LPS) on the regulation of HuR gene expression in mouse macrophages. Methods Mouse RAW264.7 macrophages were treated with multiple concentrations of glanded and glandless cottonseed extracts, gossypol and LPS for 2, 8 and 24 h. qPCR and immunoblotting were used to detect the expression of HuR mRNA and protein. Results qPCR assay showed that cottonseed extracts and LPS had minimal effect on HuR gene expression. However, gossypol increased HuR mRNA levels up to 16-fold in cells treated for 24 h. Immunoblotting confirmed that gossypol also increased HuR protein in macrophages. Conclusions These results show for the first time that gossypol is a strong stimulator of HuR gene expression and that cottonseed extracts essentially free of gossypol are probably safe to use as a reliable source of plant polyphenols. Funding Sources This work was supported by the USDA-ARS Quality and Utilization of Agricultural Products National Program 306 through CRIS 6054–41,000-103–00-D. USDA is an equal opportunity provider and employer.

Glutathione S-transferase P deficiency induces glucose intolerance via JNK-dependent enhancement of hepatic gluconeogenesis

Hepatic glutathione S-transferases (GSTs) are dysregulated in human obesity, nonalcoholic fatty liver disease, and diabetes. The multifunctional GST pi-isoform (GSTP) catalyzes the conjugation of glutathione with acrolein and inhibits c-Jun NH2-terminal kinase (JNK) activation. Herein, we tested whether GSTP deficiency disturbs glucose homeostasis in mice. Hepatic GST proteins were downregulated by short-term high-fat diet in wild-type (WT) mice concomitant with increased glucose intolerance, JNK activation, and cytokine mRNAs in the liver. Genetic deletion of GSTP did not affect body composition, fasting blood glucose levels, or insulin levels in mice maintained on a normal chow diet; however, compared with WT mice, the GSTP-null mice were glucose intolerant. In GSTP-null mice, pyruvate intolerance, reflecting increased hepatic gluconeogenesis, was accompanied by elevated levels of activated JNK, cytokine mRNAs, and glucose-6-phosphatase proteins in the liver. Treatment of GSTP-null mice with the JNK inhibitor 1,9-pyrazoloanthrone (SP600125) significantly attenuated pyruvate-induced hepatic gluconeogenesis and significantly altered correlations between hepatic cytokine mRNAs and metabolic outcomes in GSTP-null mice. Collectively, these findings suggest that hepatic GSTP plays a pivotal role in glucose handling by regulating JNK-dependent control of hepatic gluconeogenesis. Thus, hepatic GSTP-JNK dysregulation may be a target of new therapeutic interventions during early stages of glucose intolerance to prevent the worsening metabolic derangements associated with human obesity and its relentless progression to diabetes.