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Eukaryotic cells use autophagy to recycle cellular components. During autophagy, autophagosomes deliver cytoplasmic contents to the vacuole or lysosome for breakdown. Mammalian cells regulate the dynamics of autophagy via ubiquitin-mediated proteolysis of autophagy proteins. Here, we show that the Tumor necrosis factor Receptor-Associated Factor (TRAF) family proteins TRAF1a and TRAF1b (previously named MUSE14 and MUSE13, respectively) help regulate autophagy via ubiquitination. Upon starvation, cytoplasmic TRAF1a and TRAF1b translocated to autophagosomes. Knockout lines showed reduced tolerance to nutrient deficiency, increased salicylic acid and reactive oxygen species levels, and constitutive cell death in rosettes, resembling the phenotypes of autophagy-defective mutants. Starvation-activated autophagosome accumulation decreased in root cells, indicating that TRAF1a and TRAF1b function redundantly in regulating autophagosome formation. TRAF1a and TRAF1b interacted in planta with ATG6 and the RING finger E3 ligases SINAT1, SINAT2, and SINAT6 (with a truncated RING-finger domain). SINAT1 and SINAT2 require the presence of TRAF1a and TRAF1b to ubiquitinate and destabilize AUTOPHAGY PROTEIN6 (ATG6) in vivo. Conversely, starvation-induced SINAT6 reduced SINAT1- and SINAT2-mediated ubiquitination and degradation of ATG6. Consistently, / and knockout mutants exhibited increased tolerance and sensitivity, respectively, to nutrient starvation. Therefore, TRAF1a and TRAF1b function as molecular adaptors that help regulate autophagy by modulating ATG6 stability in Arabidopsis.

The yellow catfish (Pelteobagrus fulvidraco) is an economic fish with a large breeding scale, and diseases have led to huge economic losses. Tumor necrosis factor receptor-associated factors (TRAFs) are a class of intracellular signal transduction proteins that play an important role in innate and adaptive immune responses by mediating NF-κB, JNK and MAPK signaling pathways. However, there are few studies on the TRAF gene family in yellow catfish. In this study, the open reading frame (ORF) sequences of TRAF1, TRAF2a, TRAF2b, TRAF3, TRAF4a, TRAF4b, TRAF5, TRAF6 and TRAF7 genes were cloned and identified in yellow catfish. The ORF sequences of the nine TRAF genes of yellow catfish (Pf_TRAF1-7) were 1413–2025 bp in length and encoded 470–674 amino acids. The predicted protein structures of Pf_TRAFs have typically conserved domains compared to mammals. The phylogenetic relationships showed that TRAF genes are conserved during evolution. Gene structure, motifs and syntenic analyses of TRAF genes showed that the exon–intron structure and conserved motifs of TRAF genes are diverse among seven vertebrate species, and the TRAF gene family is relatively conserved evolutionarily. Among them, TRAF1 is more closely related to TRAF2a and TRAF2b, and they may have evolved from a common ancestor. TRAF7 is quite different and distantly related to other TRAFs. Real-time quantitative PCR (qRT-PCR) results showed that all nine Pf_TRAF genes were constitutively expressed in 12 tissues of healthy yellow catfish, with higher mRNA expression levels in the gonad, spleen, brain and gill. After infection with Edwardsiella ictaluri, the expression levels of nine Pf_TRAF mRNAs were significantly changed in the head kidney, spleen, gill and brain tissues of yellow catfish, of which four genes were down-regulated and one gene was up-regulated in the head kidney; four genes were up-regulated and four genes were down-regulated in the spleen; two genes were down-regulated, one gene was up-regulated, and one gene was up-regulated and then down-regulated in the gill; one gene was up-regulated, one gene was down-regulated, and four genes were down-regulated and then up-regulated in the brain. These results indicate that Pf_TRAF genes might be involved in the immune response against bacterial infection. Subcellular localization results showed that all nine Pf_TRAFs were found localized in the cytoplasm, and Pf_TRAF2a, Pf_TRAF3 and Pf_TRAF4a could also be localized in the nucleus, uncovering that the subcellular localization of TRAF protein may be closely related to its structure and function in cellular mechanism. The results of this study suggest that the Pf_TRAF gene family plays important roles in the immune response against pathogen invasion and will provide basic information to further understand the roles of TRAF gene against bacterial infection in yellow catfish.

The Epstein-Barr virus (EBV) encoded oncoprotein Latent Membrane Protein 1 (LMP1) signals through two C-terminal tail domains to drive cell growth, survival and transformation. The LMP1 membrane-proximal TES1/CTAR1 domain recruits TRAFs to activate MAP kinase, non-canonical and canonical NF-kB pathways, and is critical for EBV-mediated B-cell transformation. TRAF1 is amongst the most highly TES1-induced target genes and is abundantly expressed in EBV-associated lymphoproliferative disorders. We found that TRAF1 expression enhanced LMP1 TES1 domain-mediated activation of the p38, JNK, ERK and canonical NF-kB pathways, but not non-canonical NF-kB pathway activity. To gain insights into how TRAF1 amplifies LMP1 TES1 MAP kinase and canonical NF-kB pathways, we performed proteomic analysis of TRAF1 complexes immuno-purified from cells uninduced or induced for LMP1 TES1 signaling. Unexpectedly, we found that LMP1 TES1 domain signaling induced an association between TRAF1 and the linear ubiquitin chain assembly complex (LUBAC), and stimulated linear (M1)-linked polyubiquitin chain attachment to TRAF1 complexes. LMP1 or TRAF1 complexes isolated from EBV-transformed lymphoblastoid B cell lines (LCLs) were highly modified by M1-linked polyubiqutin chains. The M1-ubiquitin binding proteins IKK-gamma/NEMO, A20 and ABIN1 each associate with TRAF1 in cells that express LMP1. TRAF2, but not the cIAP1 or cIAP2 ubiquitin ligases, plays a key role in LUBAC recruitment and M1-chain attachment to TRAF1 complexes, implicating the TRAF1:TRAF2 heterotrimer in LMP1 TES1-dependent LUBAC activation. Depletion of either TRAF1, or the LUBAC ubiquitin E3 ligase subunit HOIP, markedly impaired LCL growth. Likewise, LMP1 or TRAF1 complexes purified from LCLs were decorated by lysine 63 (K63)-linked polyubiqutin chains. LMP1 TES1 signaling induced K63-polyubiquitin chain attachment to TRAF1 complexes, and TRAF2 was identified as K63-Ub chain target. Co-localization of M1- and K63-linked polyubiquitin chains on LMP1 complexes may facilitate downstream canonical NF-kB pathway activation. Our results highlight LUBAC as a novel potential therapeutic target in EBV-associated lymphoproliferative disorders.

The signaling adaptor TRAF1 is involved in TNFR-induced survival. Watts and colleagues demonstrate that TRAF1 also negatively regulates NF-κB activation by interfering with linear ubiquitination of the signaling subunit NEMO. TRAF1 is a signaling adaptor known for its role in tumor necrosis factor receptor-induced cell survival. Here we show that monocytes from healthy human subjects with a rheumatoid arthritis–associated single-nucleotide polymorphism (SNP) in the TRAF1 gene express less TRAF1 protein but greater amounts of inflammatory cytokines in response to lipopolysaccharide (LPS). The TRAF1 MATH domain binds directly to three components of the linear ubiquitination (LUBAC) complex, SHARPIN, HOIP and HOIL-1, to interfere with the recruitment and linear ubiquitination of NEMO. This results in decreased NF-κB activation and cytokine production, independently of tumor necrosis factor. Consistent with this, Traf1 −/− mice show increased susceptibility to LPS-induced septic shock. These findings reveal an unexpected role for TRAF1 in negatively regulating Toll-like receptor signaling, providing a mechanistic explanation for the increased inflammation seen with a disease-associated TRAF1 SNP.

In the course of apoptosis, activated caspases cleave ∼500 to ∼1,000 different proteins in a mammalian cell. The dynamics of apoptosis involve a number of previously identified, caspase-generated proapoptotic protein fragments, defined as those that increase the probability of apoptosis. In contrast to activated caspases, which can be counteracted by inhibitor of apoptosis proteins, there is little understanding of antiapoptotic responses to proapoptotic protein fragments. One possibility is the regulation of proapoptotic fragments through their selective degradation. The previously identified proapoptotic fragments Cys-RIPK1, Cys-TRAF1, Asp-BRCA1, Leu-LIMK1, Tyr-NEDD9, Arg-BID, Asp-BCL XL, Arg-BIM EL, Asp-EPHA4, and Tyr-MET bear destabilizing N-terminal residues. Tellingly, the destabilizing nature (but not necessarily the actual identity) of N-terminal residues of proapoptotic fragments was invariably conserved in evolution. Here, we show that these proapoptotic fragments are short-lived substrates of the Arg/N-end rule pathway. Metabolic stabilization of at least one such fragment, Cys-RIPK1, greatly augmented the activation of the apoptosis-inducing effector caspase-3. In agreement with this understanding, even a partial ablation of the Arg/N-end rule pathway in two specific N-end rule mutants is shown to sensitize cells to apoptosis. We also found that caspases can inactivate components of the Arg/N-end rule pathway, suggesting a mutual suppression between this pathway and proapoptotic signaling. Together, these results identify a mechanistically specific and functionally broad antiapoptotic role of the Arg/N-end rule pathway. In conjunction with other apoptosis-suppressing circuits, the Arg/N-end rule pathway contributes to thresholds that prevent a transient or otherwise weak proapoptotic signal from reaching the point of commitment to apoptosis.

The “Bermuda triangle” of genetics, environment and autoimmunity is involved in the pathogenesis of rheumatoid arthritis (RA). Various aspects of genetic contribution to the etiology, pathogenesis and outcome of RA are discussed in this review. The heritability of RA has been estimated to be about 60 %, while the contribution of HLA to heritability has been estimated to be 11–37 %. Apart from known shared epitope (SE) alleles, such as HLA-DRB1*01 and DRB1*04, other HLA alleles, such as HLA-DRB1*13 and DRB1*15 have been linked to RA susceptibility. A novel SE classification divides SE alleles into S1, S2, S3P and S3D groups, where primarily S2 and S3P groups have been associated with predisposition to seropositive RA. The most relevant non-HLA gene single nucleotide polymorphisms (SNPs) associated with RA include PTPN22 , IL23R , TRAF1 , CTLA4 , IRF5 , STAT4 , CCR6 , PADI4 . Large genome-wide association studies (GWAS) have identified more than 30 loci involved in RA pathogenesis. HLA and some non-HLA genes may differentiate between anti-citrullinated protein antibody (ACPA) seropositive and seronegative RA. Genetic susceptibility has also been associated with environmental factors, primarily smoking. Some GWAS studies carried out in rodent models of arthritis have confirmed the role of human genes. For example, in the collagen-induced (CIA) and proteoglycan-induced arthritis (PgIA) models, two important loci — Pgia26 / Cia5 and Pgia2 / Cia2 / Cia3 , corresponding the human PTPN22 / CD2 and TRAF1 / C5 loci, respectively — have been identified. Finally, pharmacogenomics identified SNPs or multiple genetic signatures that may be associated with responses to traditional disease-modifying drugs and biologics.

Stroke is a leading global cause of mortality and disability. Less than 5% of patients are able to receive tissue plasminogen activator thrombolysis within the necessary timeframe. Focusing on the process of neuronal apoptosis in the penumbra, which lasts from hours to days after ischaemia, appears to be promising. Here we report that tumour necrosis factor receptor-associated factor 1 (TRAF1) expression is markedly induced in wild-type mice 6 h after stroke onset. Using genetic approaches, we demonstrate that increased neuronal TRAF1 leads to elevated neuronal death and enlarged ischaemic lesions, whereas TRAF1 deficiency is neuroprotective. In addition, TRAF1-mediated neuroapoptosis correlates with the activation of the JNK pro-death pathway and inhibition of the Akt cell survival pathway. Finally, TRAF1 is found to exert pro-apoptotic effects via direct interaction with ASK1. Thus, ASK1 positively and negatively regulates the JNK and Akt signalling pathways, respectively. Targeting the TRAF1/ASK1 pathway may provide feasible therapies for stroke long after onset. TRAF1 is an intracellular signalling molecule that has diverse biological functions. In this study, the authors show that TRAF1 is expressed in mice soon after they have suffered a stroke and that increased TRAF1 expression increases susceptibility to ischaemia-induced apoptosis and brain injury.

A genomewide association study of North American and Swedish patients with rheumatoid arthritis who were seropositive for autoantibodies against cyclic citrullinated peptide yielded susceptibility variants in the usual suspects: HLA-DRB1 and PTPN22 . A new locus was also implicated: a SNP that lies between the TRAF1 and C5 genes. A genomewide association study of North Americans and Swedes with rheumatoid arthritis yielded susceptibility variants in the usual suspects: HLA-DRB1 and PTPN22 . A new locus was also implicated: a SNP that lies between the TRAF1 and C5 genes. Rheumatoid arthritis is a common inflammatory arthritis of unknown cause, in which both genetic and environmental risk factors have been implicated. 1 – 3 The genetic contribution to a susceptibility to rheumatoid arthritis has been shown in studies of twins 4 and families 5 and in genomewide linkage scans. 6 – 11 Two genes have shown a strong association with susceptibility: PTPN22 12 , 13 and HLA-DRB1 . 14 Variants of each gene elevate the risk primarily for a subgroup of severe rheumatoid arthritis characterized by the presence of autoantibodies against cyclic citrullinated peptide (anti–CCP-positive). 12 , 15 , 16 We have recently reported a significant association at STAT4 on chromosome 2q. . . .

Background RNA modification plays important roles in many biological processes, such as gene expression control. The aim of this study was to identify single nucleotide polymorphisms related to RNA modification (RNAm-SNPs) for rheumatoid arthritis (RA) as putative functional variants. Methods We examined the association of RNAm-SNPs with RA in summary data from a genome-wide association study of 19,234 RA cases and 61,565 controls. We performed eQTL and pQTL analyses for the RNAm-SNPs to find associated gene expression and protein levels. Furthermore, we examined the associations of gene expression and circulating protein levels with RA using two-sample Mendelian randomization analysis methods. Results A total of 160 RNAm-SNPs related to m 6 A, m 1 A, A-to-I, m 7 G, m 5 C, m 5 U and m 6 Am modifications were identified to be significantly associated with RA. These RNAm-SNPs were located in 62 protein-coding genes, which were significantly enriched in immune-related pathways. RNAm-SNPs in important RA susceptibility genes, such as PADI2 , SPRED2 , PLCL2 , HLA-A , HLA-B , HLA-DRB1 , HLA-DPB1 , TRAF1 and TXNDC11 , were identified. Most of these RNAm-SNPs showed eQTL effects, and the expression levels of 26 of the modifiable genes (e.g., PADI2 , TRAF1 , HLA-A , HLA-DRB1 , HLA-DPB1 and HLA-B ) in blood cells were associated with RA. Circulating protein levels, such as CFB, GZMA, HLA-DQA2, IL21, LRPAP1 and TFF3, were affected by RNAm-SNPs and were associated with RA. Conclusion The present study identified RNAm-SNPs in the reported RA susceptibility genes and suggested that RNAm-SNPs may affect RA risk by affecting the expression levels of corresponding genes and proteins.

Background Infantile pneumonia (IP) is a leading cause of morbidity and mortality in children worldwide, with limited treatment options. Tumor necrosis factor receptor-associated factor 1 (TRAF1) has been implicated in the pathogenesis of various inflammatory diseases. Given the lack of effective therapies in IP, understanding the role of TRAF1 in regulating IP is crucial for developing new therapeutic strategies. Methods This study utilized in vitro and in vivo models to investigate the role of TRAF1 in IP. WI-38 cells were stimulated with lipopolysaccharide (LPS), and rats were administered LPS to mimic IP. The mRNA expression of TRAF1 and Sp1 transcription factor (SP1) was analyzed using quantitative real-time polymerase chain reaction. The protein expression of TRAF1, ubiquitin-specific peptidase 7 (USP7), and SP1 was detected by western blotting. Cell viability and apoptosis were assessed using cell counting kit-8 assay and flow cytometry/TUNEL assays, respectively. Interleukin-6 and tumor necrosis factor-α levels were measured by enzyme-linked immunosorbent assays. Reactive oxygen species and malondialdehyde levels were analyzed using fluorescence microscopy and colorimetric assays. The interactions among USP7, TRAF1, and SP1 were identified using co-immunoprecipitation assay, immunofluorescence assay, and dual-luciferase reporter assay. TRAF1 silencing-induced effects were validated in a rat model. Lung tissue pathology was assessed using haematoxylin and eosin assay and Massion assay. Results LPS treatment induced apoptosis, inflammation, and oxidative stress of WI-38 cells, however, TRAF1 silencing ameliorated these effects. USP7 stabilized TRAF1 protein expression through its deubiquitinating activity, while TRAF1 overexpression reversed the effects of USP7 silencing in LPS-treated WI-38 cells. In addition, SP1 transcriptionally activated TRAF1 in WI-38 cells. Further, TRAF1 silencing improved lung injury in LPS-induced mice. Conclusion Activation of TRAF1 by USP7/SP1 exacerbated the severity of IP, suggesting that targeting TRAF1 may have significant clinical implications for the treatment of IP.