UBL4A Augments Innate Immunity by Promoting the K63-Linked Ubiquitination of TRAF6

Peng, Shengnan; Yao, Ran-Ran; Yu, Shuang-Shuang; Chen, Liqun; Pang, Xuewen; Zhang, Jun

doi:10.4049/jimmunol.1800750

Cited by 7 publications

(4 citation statements)

References 58 publications

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“…Ubl4A is a multifunctional protein that is involved in diverse cellular events, from translocation of newly synthesized proteins to the ER, DNA damage repair, bone modeling, inflammatory and innate immune response, to anti-tumorigenesis [40][41][42][43][44][45][46][47][48]. Here, we showed that under nutrient starvation conditions, Ubl4A functions as a survival factor mainly by regulating the mitochondrial fusion process.…”

Section: Discussionmentioning

confidence: 97%

“…Although it belongs to the ubiquitin-like family, Ubl4A has no ubiquitination activity [39]. Instead, this protein has diverse functions, from chaperoning nascent synthesized proteins to the ER, promoting anti-tumorigenesis, potentiating autoimmune diseases, to augmenting innate immune response through NFκB signaling pathway [40][41][42][43][44][45][46][47][48]. We have shown that Ubl4A can directly interact with the Arp2/3 complex to promote actin branching [49].…”

Section: Introductionmentioning

confidence: 99%

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Ubl4A is critical for mitochondrial fusion process under nutrient deprivation stress

et al. 2020

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Mitochondrial fusion and fission are dynamic processes regulated by the cellular microenvironment. Under nutrient starvation conditions, mitochondrial fusion is strengthened for energy conservation. We have previously shown that newborns of Ubl4A-deficient mice were more sensitive to starvation stress with a higher rate of mortality than their wild-type littermates. Ubl4A binds with the actin-related protein Arp2/3 complex to synergize the actin branching process. Here, we showed that deficiency in Ubl4A resulted in mitochondrial fragmentation and apoptosis. A defect in the fusion process was the main cause of the mitochondrial fragmentation and resulted from a shortage of primed Arp2/3 complex pool around the mitochondria in the Ubl4A-deficient cells compared to the wild-type cells. As a result, the mitochondrial fusion process was not undertaken quickly enough to sustain starvation stress-induced cell death. Consequently, fragmented mitochondria lost their membrane integrity and ROS was accumulated to trigger caspase 9-dependent apoptosis before autophagic rescue. Furthermore, the wild-type Ubl4A, but not the Arp2/3-binding deficient mutant, could rescue the starvation-induced mitochondrial fragmentation phenotype. These results suggest that Ubl4A promotes the mitochondrial fusion process via Arp2/3 complex during the initial response to nutrient deprivation for cell survival.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Ubl4A is critical for mitochondrial fusion process under nutrient deprivation stress

et al. 2020

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“…regulating a series of physiological process (35)(36)(37)(38)(39)(40). In addition, the oncogenic role of TRAF6 in tumors has been widely reported.…”

Section: Discussionmentioning

confidence: 99%

TRAF6 Regulates the Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Tumor-Bearing Host

et al. 2021

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Myeloid-derived suppressor cells (MDSCs) are immature heterogeneous cells derived from the bone marrow and they are the major component of the tumor-induced immunosuppressive environment. Tumor necrosis factor receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase, catalyzes the polyubiquitination of target proteins. TRAF6 plays a critical role in modulating the immune system. However, whether TRAF6 is involved in the regulation of MDSCs has not been thoroughly elucidated to date. In this study, we found that the expression of TRAF6 in MDSCs derived from tumor tissue was significantly upregulated compared with that of MDSCs from spleen of tumor-bearing mice. Knockdown of TRAF6 remarkably attenuated the immunosuppressive effects of MDSCs. Mechanistically, TRAF6 might improve the immunosuppression of MDSCs by mediating K63-linked polyubiquitination and phosphorylation of signal transducer and activator of transcription 3 (STAT3). Additionally, it was discovered that the accumulation of MDSCs was abnormal in peripheral blood of lung cancer patients. TRAF6 and arginase 1 were highly expressed in MDSCs of patients with lung cancer. Taken together, our study demonstrated that TRAF6 participates in promoting the immunosuppressive function of MDSCs and provided a potential target for antitumor immunotherapy.

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“…For example, the viral nucleic acid sensor RIG-I is activated by K63-polyubiquitination mediated by the ligases TRIM4 [ 45 ], Riplet [ 46 ], and TRIM25 [ 47 ], while signaling is terminated by K48-polyubiquitination mediated by the Ring Finger protein 125 (RNF125) ligase [ 48 ], which promotes proteasomal degradation. The attachment of M1- or K63-polyubiquitin chains to signaling mediators such as IRAK1 (Interleukin 1 associated kinase-1) [ 49 , 50 ], TRAF6 [ 51 ], RIP1 (Receptor interacting protein-1) [ 52 ], TRAF3 (TNF receptor associated factor-3) [ 53 ], MAVS (Mitochondrial antiviral signaling protein) [ 54 ], NEMO (NF-κB essential modulator) [ 55 ], and STING (Stimulator of IFN genes) [ 56 ] promotes activation of the kinases IKK (IκB kinase), TAK1 (Transforming growth factor beta activated kinase-1), and TBK1 (TANK binding kinase-1) [ 57 , 58 ] that phosphorylate the executor transcription factors NF-κB (Nuclear factor-κB, IRF3 (Interferon regulatory factor-3), and IRF7, leading to their activation and nuclear translocation. Phosphorylation may also serve as a signal for ubiquitination as illustrated by the phosphorylation-dependent K48-polyubiquitination of IκBα by the βTRCP E3 ligase, which leads to degradation of the inhibitor and activation of NF-κB [ 59 ].…”

Section: Ubls In Viral Infectionmentioning

confidence: 99%

Viral Ubiquitin and Ubiquitin-Like Deconjugases—Swiss Army Knives for Infection

Masucci

2020

Biomolecules

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Posttranslational modifications of cellular proteins by covalent conjugation of ubiquitin and ubiquitin-like polypeptides regulate numerous cellular processes that are captured by viruses to promote infection, replication, and spreading. The importance of these protein modifications for the viral life cycle is underscored by the discovery that many viruses encode deconjugases that reverse their functions. The structural and functional characterization of these viral enzymes and the identification of their viral and cellular substrates is providing valuable insights into the biology of viral infections and the host’s antiviral defense. Given the growing body of evidence demonstrating their key contribution to pathogenesis, the viral deconjugases are now recognized as attractive targets for the design of novel antiviral therapeutics.

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UBL4A Augments Innate Immunity by Promoting the K63-Linked Ubiquitination of TRAF6

Cited by 7 publications

References 58 publications

Ubl4A is critical for mitochondrial fusion process under nutrient deprivation stress

Ubl4A is critical for mitochondrial fusion process under nutrient deprivation stress

TRAF6 Regulates the Immunosuppressive Effects of Myeloid-Derived Suppressor Cells in Tumor-Bearing Host

Viral Ubiquitin and Ubiquitin-Like Deconjugases—Swiss Army Knives for Infection

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