The intensity and duration of macrophage-mediated inflammatory responses are controlled by proteins that modulate inflammatory signaling pathways. MCPIP1 (monocyte chemotactic protein–induced protein 1), a recently identified CCCH Zn finger–containing protein, plays an essential role in controlling macrophage-mediated inflammatory responses. However, its mechanism of action is poorly understood. In this study, we show that MCPIP1 negatively regulates c-Jun N-terminal kinase (JNK) and NF-κB activity by removing ubiquitin moieties from proteins, including TRAF2, TRAF3, and TRAF6. MCPIP1-deficient mice spontaneously developed fatal inflammatory syndrome. Macrophages and splenocytes from MCPIP1^−/− mice showed elevated expression of inflammatory gene expression, increased JNK and IκB kinase activation, and increased polyubiquitination of TNF receptor–associated factors. In vitro assays directly demonstrated the deubiquitinating activity of purified MCPIP1. Sequence analysis together with serial mutagenesis defined a deubiquitinating enzyme domain and a ubiquitin association domain in MCPIP1. Our results indicate that MCPIP1 is a critical modulator of inflammatory signaling.

Endothelial activation plays an essential role in the pathogenesis of sepsis-induced acute lung injury, however, the detailed regulatory mechanisms remain largely unknown. Here, we reported that TRIM47, an E3 ubiquitin ligase of the tripartite motif-containing protein family, was highly expressed in vascular endothelial cells. TRIM47-deficient mice were effectively resistant to lipopolysaccharide (LPS)-induced acute lung injury and death by attenuating pulmonary inflammation. TRIM47 was upregulated during TNFα-induced endothelial activation in vitro. Knockdown of TRIM47 in endothelial cells inhibited the transcription of multiple pro-inflammatory cytokines, reduced monocyte adhesion and the expression of adhesion molecules, and suppressed the secretion of IL-1β and IL-6 in endothelial cells. By contrast, overexpression of TRIM47 promoted inflammatory response and monocyte adhesion upon TNFα stimulation. In addition, TRIM47 was able to activate the NF-κB and MAPK signaling pathways during endothelial activation. Furthermore, our experiments revealed that TRIM47 resulted in endothelial activation by promoting the K63-linked ubiquitination of TRAF2, a key component of the TNFα signaling pathway. Taken together, our studies demonstrated that TRIM47 as a novel activator of endothelial cells, promoted LPS-induced pulmonary inflammation and acute lung injury through potentiating the K63-linked ubiquitination of TRAF2, which in turn activates NF-κB and MAPK signaling pathways to trigger an inflammatory response in endothelial cells.

Coronavirus disease 2019 (COVID-19), caused by the betacoronavirus SARS-CoV-2, is a worldwide challenge for health care systems. The leading cause of mortality in patients with COVID-19 is hypoxic respiratory failure from acute respiratory distress syndrome (ARDS).

Significance: Here, we present data showing that monocyte chemotactic protein-induced protein 1 (MCPIP1) acts as an RNase to limit HIV-1 production in resting CD4+ T cells. Unlike those previously identified factors with restrictions that tend to be overcome by virally encoded proteins, MCPIP1 becomes rapidly degraded on activation of human CD4+ T cells. These findings provide insights into the mechanisms of cellular activation-mediated HIV-1 production in CD4+ T cells and represent a breakthrough in the relevant field.

The molecular mechanism to regulate energy balance is not completely understood. Here we observed that Egr-1 expression in white adipose tissue (WAT) was highly correlated with dietary-induced obesity and insulin resistance both in mice and humans. Egr-1 null mice were protected from diet-induced obesity and obesity-associated pathologies such as fatty liver, insulin resistance, hyperlipidemia and hyperinsulinemia. This phenotype can be largely explained by the increase of energy expenditure in Egr-1 null mice. Characterization of these mice revealed that the expression of FOXC2 and its target genes were significantly elevated in white adipose tissues, leading to WAT energy expenditure instead of energy storage. Altogether, these studies suggest an important role for Egr-1, which, by repressing FOXC2 expression, promotes energy storage in WAT and favored the development of obesity under high energy intake.