Regulation of the linear ubiquitination of STAT1 controls antiviral interferon signaling

Zuo, Yibo; Feng, Qian; Jin, Lincong; Huang, Fan; Miao, Ying; Liu, Jin; Xu, Ying; Chen, Xiangjie; Zhang, Honggang; Guo, Tingting; Yuan, Yukang; Zhang, Liting; Wang, Jun; Zheng, Hui

doi:10.1038/s41467-020-14948-z

Cited by 85 publications

(79 citation statements)

References 34 publications

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“…In addition, it can also be observed that viruses stimulate expression of some cellular proteins independently of IFN-I signaling. For example, viral infection stimulated HOIP protein expression dependently on the NF-κB but not IFN-I pathways (Zuo et al, 2020). Cellular OTUD1 proteins were upregulated by viral infection in a NF-κB-dependent manner (Zhang et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Myc-c-Cbl C382A mutant was generated by Quick-Change site-Directed Mutagenesis Kit (Stratagene). HA-ubiquitin (HA-Ub), HA-R48K and HA-R63K (all lysins on the ubiquitin gene are mutated to arginines except the corresponding lysine) were described as previously (Guo et al, 2019;Yuan et al, 2020;Zuo et al, 2020). HIV-1 (pNL4-3), HIV-1 ( Nef) and VSVG were from Dr. Chunsheng Dong (Soochow University, China).…”

Section: Plasmids and Reagentsmentioning

confidence: 99%

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Ubiquitin E3 Ligase c-Cbl Is a Host Negative Regulator of Nef Protein of HIV-1

et al. 2020

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Nef is an accessory protein encoded by human immunodeficiency virus type-1 (HIV-1) and plays important roles in regulating HIV-1 infection and viral replication. Interestingly, HIV-1 Nef can promote degradation of numerous host proteins to disrupt cellular antiviral immune response. However, how HIV-1 Nef is degraded by host factors remains largely unexplored. Here, we identified c-Cbl as a host ubiquitin E3 ligase of HIV-1 Nef. We found that c-Cbl interacts with Nef and reduces protein levels of HIV-1 Nef. Further studies demonstrated that c-Cbl promoted Lys48-linked polyubiquitination of HIV-1 Nef, thus attenuating protein stability of HIV-1 Nef. Importantly, cellular c-Cbl ubiquitinated and degraded Nef proteins produced by HIV-1 NL4-3 virions, and ultimately attenuated HIV-1 virulence for infection of THP1 cells. This study reveals a ubiquitination and proteasome-dependent degradation mechanism of HIV-1 Nef protein, and could provide potential strategies for fighting against HIV-1.

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Section: Discussionmentioning

confidence: 99%

Section: Plasmids and Reagentsmentioning

confidence: 99%

Ubiquitin E3 Ligase c-Cbl Is a Host Negative Regulator of Nef Protein of HIV-1

et al. 2020

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“…LUBAC and the linear ubiquitination activity reportedly down-regulate the type I IFN production pathway [66,67]. STAT1 is linearly ubiquitinated at the K511 and K652 residues by LUBAC, which inhibits binding to the type I IFN receptor, IFNAR2, and the linear ubiquitination of STAT1 is removed by OTULIN [68]. By contrast, virus infection induces the enhanced LUBAC-mediated NF-κB activation, which in turn, inhibits IFN-STAT1 signaling.…”

Section: Lubac-mediated Regulation Of Interferon Signalingmentioning

confidence: 99%

Linear Ubiquitin Code: Its Writer, Erasers, Decoders, Inhibitors, and Implications in Disorders

Oikawa

Sato

Ito

et al. 2020

IJMS

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The linear ubiquitin chain assembly complex (LUBAC) is a ubiquitin ligase composed of the Heme-oxidized IRP2 ubiquitin ligase-1L (HOIL-1L), HOIL-1L-interacting protein (HOIP), and Shank-associated RH domain interactor (SHARPIN) subunits. LUBAC specifically generates the N-terminal Met1-linked linear ubiquitin chain and regulates acquired and innate immune responses, such as the canonical nuclear factor-κB (NF-κB) and interferon antiviral pathways. Deubiquitinating enzymes, OTULIN and CYLD, physiologically bind to HOIP and control its function by hydrolyzing the linear ubiquitin chain. Moreover, proteins containing linear ubiquitin-specific binding domains, such as NF-κB-essential modulator (NEMO), optineurin, A20-binding inhibitors of NF-κB (ABINs), and A20, modulate the functions of LUBAC, and the dysregulation of the LUBAC-mediated linear ubiquitination pathway induces cancer and inflammatory, autoimmune, and neurodegenerative diseases. Therefore, inhibitors of LUBAC would be valuable to facilitate investigations of the molecular and cellular bases for LUBAC-mediated linear ubiquitination and signal transduction, and for potential therapeutic purposes. We identified and characterized α,β-unsaturated carbonyl-containing chemicals, named HOIPINs (HOIP inhibitors), as LUBAC inhibitors. We summarize recent advances in elucidations of the pathophysiological functions of LUBAC-mediated linear ubiquitination and identifications of its regulators, toward the development of LUBAC inhibitors.

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“…In innate and adaptive immunity, OTULIN is an essential negative regulator of LUBAC, which hydrolyzes LUBAC induced Met-1 lineal ubiquitination to prevent NF-κB-or TNF-induced inflammation augmentation [71][72][73]127]. OTULIN can also control antiviral signaling by regulating the lineal ubiquitination chain of STAT1 [74]. For the negative role of OTULIN in immune responses, OTULIN deficiency might cause auto-inflammatory syndrome [128].…”

Section: Otusmentioning

confidence: 99%

The Role of Deubiquitinating Enzymes in Acute Lung Injury and Acute Respiratory Distress Syndrome

Zou

2020

IJMS

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Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) are characterized by an inflammatory response, alveolar edema, and hypoxemia. ARDS occurs most often in the settings of pneumonia, sepsis, aspiration of gastric contents, or severe trauma. The prevalence of ARDS is approximately 10% in patients of intensive care. There is no effective remedy with mortality high at 30–40%. Most functional proteins are dynamic and stringently governed by ubiquitin proteasomal degradation. Protein ubiquitination is reversible, the covalently attached monoubiquitin or polyubiquitin moieties within the targeted protein can be removed by a group of enzymes called deubiquitinating enzymes (DUBs). Deubiquitination plays an important role in the pathobiology of ALI/ARDS as it regulates proteins critical in engagement of the alveolo-capillary barrier and in the inflammatory response. In this review, we provide an overview of how DUBs emerge in pathogen-induced pulmonary inflammation and related aspects in ALI/ARDS. Better understanding of deubiquitination-relatedsignaling may lead to novel therapeutic approaches by targeting specific elements of the deubiquitination pathways.

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Regulation of the linear ubiquitination of STAT1 controls antiviral interferon signaling

Cited by 85 publications

References 34 publications

Ubiquitin E3 Ligase c-Cbl Is a Host Negative Regulator of Nef Protein of HIV-1

Ubiquitin E3 Ligase c-Cbl Is a Host Negative Regulator of Nef Protein of HIV-1

Linear Ubiquitin Code: Its Writer, Erasers, Decoders, Inhibitors, and Implications in Disorders

The Role of Deubiquitinating Enzymes in Acute Lung Injury and Acute Respiratory Distress Syndrome

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