Search

While most NOD‐like receptors (NLRs) are predominately expressed by innate immune cells, NLRC3, an inhibitory NLR of immune signaling, exhibits the highest expression in lymphocytes. The role of NLRC3 or any NLRs in B lymphocytes is completely unknown. Gammaherpesviruses, including human Epstein–Barr virus (EBV) and murine gammaherpesvirus 68 (MHV‐68), establish latent infection in B lymphocytes, which requires elevated NF‐κB. This study shows that during latent EBV infection of human B cells, viral‐encoded latent membrane protein 1 (LMP1) decreases NLRC3 transcript. LMP1‐induced‐NF‐κB activation suppresses the promoter activity of NLRC3 via p65 binding to the promoter. Conversely, NLRC3 inhibits NF‐κB activation by promoting the degradation of LMP1 in a proteasome‐dependent manner. In vivo, MHV‐68 infection reduces Nlrc3 transcripts in splenocytes, and Nlrc3‐deficient mice show greater viral latency than controls. These results reveal a bidirectional regulatory circuit in B lymphocytes, where viral latent protein LMP1 reduces NLRC3 expression, while NLRC3 disrupts gammaherpesvirus latency, which is an important step for tumorigenesis. [ABSTRACT FROM AUTHOR]

Few studies about nucleotide‐oligomerization domain‐like receptor subfamily C3 (NLRC3) in PASMCs have been conducted. This research aimed to investigate the role of NLRC3 on platelet‐derived growth factor (PDGF)‐induced proliferation of pulmonary artery smooth muscle cells (PASMCs) and its underlying mechanism. We found that the proliferation of PASMCs stimulated with PDGF decreased when phosphoinositide 3‐kinase (PI3K) or mammalian target of rapamycin (mTOR) inhibitors pretreatment. Overexpression of NLRC3 inhibited the proliferation of PASMCs and the phosphorylation of PI3K and mTOR while knocking down NLRC3 reversed this effect. Targeted to PI3K or mTOR can also reverse the effect of NLRC3. Activation of PI3K increased the phosphorylation of mTOR while inhibition of PI3K reduced it. Our data suggest that PDGF can induce abnormal proliferation of PASMCs, and NLRC3 suppresses activation of the PI3K‐mTOR signaling thus inhibits PASMCs proliferation. These findings unveiled the effect of NLRC3 as an inhibitor of the PI3K‐mTOR pathway mediating protection against PASMCs proliferation. [ABSTRACT FROM AUTHOR]

Nucleotide‐binding domain, leucine‐rich repeat family with a caspase activation and recruitment domain 3 (NLRC3) participates in both immunity and cancer. The aim of this study was to determine the role of NLRC3 in human hepatocellular carcinoma (HCC) and the underlying mechanisms. We collected human liver tissues from nonalcoholic steatohepatitis (NASH), HCC, and adjacent normal tissues to characterize the pattern of NLRC3 expression by real‐time quantitative polymerase chain reaction and immunohistochemistry. Then, we used the HCC cell line, HuH‐7, transfected with small interfering RNA to silence the NLRC3 expression. 5‐Ethynyl‐2'‐deoxyuridine assay, scratch assay, and transwell invasion assay were used for assessing proliferation, migration, and invasion, respectively. Flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay were conducted to assess cell apoptosis. The expression of NLRC3 was reduced in human HCC tissues, compared with normal liver and nonalcoholic steatohepatitis tissues. After knocking down of NLRC3, the proliferation, migration, and invasion were increased in HuH‐7 cells. And flow cytometry and TUNEL assay showed that HuH‐7 cell apoptosis was suppressed after NLRC3 knockdown. As for the underlying mechanisms, knockdown of NLRC3 in HuH‐7 cells was associated with the activation of Janus kinase 2/signal transducers and activators of transcription 3 (JAK2/STAT3) pathway under interleukin‐6 (IL‐6) stimulation. NLRC3 expression was downregulated in human HCC tissues. NLRC3 silencing in HuH‐7 cells can promote the proliferation, migration, and invasion of hepatocellular carcinoma cells. JAK2/STAT3 pathway activation induced by IL‐6 may be the underlying mechanism for HCC when NLRC3 expression is silenced. And the invasion of HuH‐7 cells was partially suppressed by the STAT3 specific inhibitor (cryptotanshinone). Therefore, NLRC3 may play a significant role in HCC and might be a therapeutic target for the treatment of HCC. [ABSTRACT FROM AUTHOR]

Phosphoinositide 3‐kinase (PI3K) activation plays a critical role in the pulmonary vascular remodeling of pulmonary hypertension (PH). The nucleotide‐oligomerization domain (NOD)‐like receptor subfamily C3 (NLRC3) inhibits proliferation and inflammation via PI3K signaling in cancer. We previously showed NLRC3 was significantly reduced in PH patients, but the mechanism of function remains unclear. This study aimed to determine the potential role of NLRC3 in PH. We found that NLRC3 was downregulated in the pulmonary arteries of PH animal models and platelet‐derived growth factor‐BB (PDGF‐BB) stimulated pulmonary arterial smooth muscle cells (PASMCs). NLRC3 pretreatment reduced right ventricular systolic pressure, attenuated pulmonary vascular remodeling and RVHI, and ameliorated proliferation, migration, and inflammation. Monocrotaline (MCT)‐ and PDGF‐BB‐mediated PI3K activation were suppressed by NLRC3 pretreatment. 740Y‐P decreased the effect of NLRC3. Collectively, NLRC3 protected against MCT‐induced rat PH and PDGF‐BB‐induced PASMC proliferation, migration, and inflammation through a mechanism involving PI3K inhibition. NLRC3 may have a therapeutic effect on PH and provide a promising therapeutic strategy for PH. [ABSTRACT FROM AUTHOR]