TRAF5 splicing variants associate with TRAF3 and RIP1 in NF-κB and type I IFN signaling in large yellow croaker Larimichthys crocea.

As an adaptor protein functions essentially in the activation of NF-κΒ and MAPK signaling pathways mediated by NOD1 and NOD2, RIP2 plays important roles in the host innate immune responses. In the present study, the RIP2 ortholog termed Lc-RIP2 was identified and characterized in large yellow croaker (Larimichthys crocea). It was revealed that Lc-RIP2 is consisted of an open reading frame (ORF) of 1695 bp, encoding a protein of 564 aa, with an N-terminal kinase domain and a C-terminal caspase activation and recruitment domain (CARD). Subcellular localization assays demonstrated that Lc-RIP2 was a cytosolic protein, which was broadly distributed in the examined tissues/organs, and could be induced in response to poly I:C, LPS, PGN, and Pseudomonas plecoglossicida stimulations in vivo according to qRT-PCR analysis. Notably, Lc-RIP2 overexpression in vitro was sufficient to abolish SVCV proliferation in EPC cells, and could significantly induce the activation of NF-κB, IRF3, IRF7, and IFN1 promoters. In addition, luciferase assays found that Lc-RIP2 could cooperate with Lc-MAVS, Lc-TRAF3, Lc-TRAF6, Lc-IRF3, and Lc-IRF7 in NF-κB activation, associate with Lc-TRIF, Lc-MAVS, Lc-TRAF3, Lc-IRF3, and Lc-IRF7 in IRF3 activation, enhance Lc-TRIF, Lc-MAVS, Lc-TRAF3, and Lc-TRAF6 mediated IRF7 activation, and Lc-IRF3 mediated IFN1 activation, whereas suppress NF-κB activation when co-expressed with Lc-TRIF. Co-immunoprecipitation (Co-IP) assays also demonstrated that Lc-RIP2 interacts separately with Lc-TRIF, Lc-MAVS, Lc-TRAF3, Lc-TRAF6, Lc-IRF3, and Lc-IRF7. It is thus collectively indicated that Lc-RIP2 function dominantly in the regulation of the host innate immune signaling. 

Functional characterization of RIP2 in large yellow croaker (Larimichthys crocea), a protein involved in the host antiviral responses via NF-κΒ, IRF3/7 related signaling.

Tumor necrosis factor receptor-associated factors (TRAFs) play vital roles in tumor necrosis factor receptor (TNF-R) and interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) mediated signaling pathway. However, the role that TRAF7 plays in the host immune responses is largely unknown in comparison to the extensive and in-depth research that has been conducted on other members of the TRAF family. Notably, Lc-TRAF7, a cloned TRAF7 ortholog, was discovered in the large yellow croaker (Larimichthys crocea) in the current study, which has an open reading frame (ORF) of 1,962 base pairs and encodes a protein of 653 amino acids (aa). Lc-TRAF7 is consisted of a RING finger domain, a coiled-coil domain, and seven WD40 domains, with the genomic organization consisted of 20 exons and 19 introns. According to the expression analysis, Lc-TRAF7 was presented in a wide range of detected organs and tissues of the healthy fish, and was able to significantly induced by stimulations of poly I:C, LPS, PGN, and Pseudomonas plecoglossicida infection. Subcellular distribution analysis revealed that Lc-TRAF7 was a cytoplasmic protein, with the RING finger and coiled-coil domain function importantly in its subcellular localization. Luciferase assays demonstrated that Lc-TRAF7 overexpression significantly induced the activation of NF-κB, IRF3, IRF7, and IFN1 promoters. In addition, the WD40 domains play a pivotal role in the NF-κB promoter activation, whereas the RING finger and coiled-coil domain were essential in the IRF3, IRF7, and IFN1 promoter activation. Notably, Lc-TRAF7 overexpression could suppress SVCV proliferation in EPC cells, and the expression levels of IRF3, IRF7, ISG15, ISG56, RSAD2, and TNF-α were up-regulated under Lc-TRAF7 overexpression in LYCMS cells. These findings collectively implied that Lc-TRAF7 may function as an important regulator in the host antiviral responses via the NF-κB as well as IRF3/7 involved signaling pathways.

/pdf/teleost-traf7-a-protein-functions-in-the-host-antiviral-3sl3822k.pdf

Teleost TRAF7, a protein functions in the host antiviral responses via NF-κB and IRF3/7 mediated signaling

BACKGROUND
Sterile alpha and TIR motif-containing 1 (Sarm1) is known as a negative regulator of inflammatory responses. However, its role in inflammatory bowel disease (IBD) is still unclear.


OBJECTIVE
This study aimed to explore the function of Sarm1 in IBD and its underlying mechanisms. Sarm1 and tumor necrosis factor (TNF) receptor associated factor 3 (TRAF3) knockout (KO) micewere established.


METHODS
The colitis was induced using dextran sulfate sodium (DSS). Bone marrow-derived macrophages (BMDMs) were isolated and stimulated with lipopolysaccharides (LPS) or cytidine phosphate guanosine(CpG). Inflammatory cytokines were measured viaELISA. qPCR and Western blotting were used to determine the levels of the mRNA and protein expression, respectively.


RESULTS
It was demonstrated that reduced expression of Sarm1 was correlated with the severity of IBD in ulcerative colitis patients, and also with the reduction of pro-inflammatory cytokines in the mouse model induced by DSS. It was further observed that Sarm1 KO enhanced the induction of pro-inflammatory cytokines in both animal and in vitro cell models. Sarm1 deficiency in macrophages increased the severity of colitis in the mouse model induced by DSS. Moreover, Sarm1 regulatedTRAF3 recruitment to myeloid differentiation primary response protein 88 (MyD88), which in turn controlled the MYD88-mediated inflammatory responses.


CONCLUSIONS
In summary, our data suggest that Sarm1 controls the MYD88-mediated inflammatory responses in IBD via its regulation of TRAF3 recruitment.

Sarm1 Controls the MYD88-Mediated Inflammatory Responses in Inflammatory Bowel Disease via the Regulation of TRAF3 Recruitment.

Hyperuricemia nephropathy, also known as gouty nephropathy, refers to renal damage induced by hyperuricemia caused by excessive production of serum uric acid or low excretion of uric acid. the persistence of symptoms will lead to changes in renal tubular phenotype and accelerate the progress of renal fibrosis. The existence and progressive aggravation of symptoms will bring a heavy burden to patients, their families and society, affect their quality of life and reduce their well-being. With the increase of reports on hyperuricemia nephropathy, the importance of related signal pathways in the pathogenesis of hyperuricemia nephropathy is becoming more and more obvious, but most studies are limited to the upper and lower mediating relationship between 1 or 2 signal pathways. The research on the comprehensiveness of signal pathways and the breadth of crosstalk between signal pathways is limited. By synthesizing the research results of signal pathways related to hyperuricemia nephropathy in recent years, this paper will explore the specific mechanism of hyperuricemia nephropathy, and provide new ideas and methods for the treatment of hyperuricemia nephropathy based on a variety of signal pathway crosstalk and personal prospects. 

Possible correlated signaling pathways with chronic urate nephropathy: A review

As a TIR domain-containing molecular, sterile α-and armadillo motif-containing protein (SARM) acts as an adaptor in Toll-like receptor (TLR) signaling, and also plays important roles in mediating apoptosis and neuronal injury. In the present study, the ortholog of SARM, named as Lc-SARM, was cloned and identified in large yellow croaker (Larimichthys crocea). The full-length ORF of Lc-SARM consists of 2,154 bp, encoding a protein of 717 amino acids (aa), which is comprised of an N-terminal ARM domain, two SAM domains, and a C-terminal TIR domain. Confocal microscopy revealed that Lc-SARM was mainly distributed in the cytoplasm, and the mRNA expression level of Lc-SARM was broadly distributed in all the detected organs/tissues, with the highest expression level found in the brain. The expression patterns of Lc-SARM could be induced in response to poly I:C, LPS, PGN stimulations, and Pseudomonas plecoglossicida infection. Notably, although the overexpression of Lc-SARM could significantly induce NF-κB, IRF3, IRF7, and type I IFN promoter activation, whereas the co-expression of Lc-SARM with Lc-TRIF, Lc-TRAF3, Lc-IRF3, or Lc-IRF7 significantly down-regulated the induction of NF-κB, IRF3, IRF7, or type I IFN promoter activation, and suppressed the antiviral effects as well as the downstream antiviral-related genes expression compared to the only overexpression of Lc-TRIF, Lc-TRAF3, Lc-IRF3, or Lc-IRF7. Co-immunoprecipitation (Co-IP) assays also demonstrated that Lc-SARM interacts separately with Lc-TRIF, Lc-TRAF3, Lc-IRF3, and Lc-IRF7. It is thus collectively suggested that Lc-SARM functions as a negative regulator in Lc-TRIF, Lc-TRAF3, and Lc-IRF3/7 involved antiviral signaling.

/pdf/sarm-suppresses-trif-traf3-and-irf3-7-mediated-antiviral-3s1fnuco.pdf

SARM suppresses TRIF, TRAF3, and IRF3/7 mediated antiviral signaling in large yellow croaker Larimichthys crocea

NLRC3 regulates RIP2, STING, TBK1, and TRAF6 mediated type I IFN signaling and inflammatory response in large yellow croaker Larimichthys crocea.

Molecular cloning and functional characterization of RIP1 in large yellow croaker Larimichthys crocea.

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Papers

SARM suppresses TRIF, TRAF3, and IRF3/7 mediated antiviral signaling in large yellow croaker Larimichthys crocea

Functional characterization of RIP2 in large yellow croaker (Larimichthys crocea), a protein involved in the host antiviral responses via NF-κΒ, IRF3/7 related signaling.

NLRC3 regulates RIP2, STING, TBK1, and TRAF6 mediated type I IFN signaling and inflammatory response in large yellow croaker Larimichthys crocea.

Molecular cloning and functional characterization of RIP1 in large yellow croaker Larimichthys crocea.