The Kinase MAP4K1 Inhibits Cytosolic RNA-Induced Antiviral Signaling by Promoting Proteasomal Degradation of TBK1/IKKε

He, Tian‐Sheng; Huang, Jing-Ping; Tian, Chen; Zhang, Zhi; Cai, Kuntai; Yu, Jingge; Xu, Liang‐Guo

doi:10.1128/spectrum.01458-21

Cited by 12 publications

(7 citation statements)

References 55 publications

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“…MAPKs, not just MAP3Ks, play an important role in regulating IFN-I production. MAP4K1 inhibits IFN-I production by targeting TBK1/IKKε [ 175 ], while p38 MAPK reportedly inhibits STING activation by increasing phosphorylation of USP21 at Ser538, thus further controlling the IFN-I pathway [ 176 ]. JNK activation is crucial for the proper functioning of the IFN-I pathway [ 113 , 177 ].…”

Section: Discussion and Perspectivesmentioning

confidence: 99%

Functions of MAP3Ks in antiviral immunity

et al. 2023

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Immune signal transduction is crucial to the body’s defense against viral infection. Recognition of pathogen-associated molecular patterns by pattern recognition receptors (PRRs) activates the transcription of interferon regulators and nuclear factor-κB (NF-κB); this promotes the release of interferons and inflammatory factors. Efficient regulation of type I interferon and NF-κB signaling by members of the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family plays an important role in antiviral immunity. Elucidating the specific roles of MAP3K activation during viral infection is essential to develop effective antiviral therapies. In this review, we outline the specific regulatory mechanisms of MAP3Ks in antiviral immunity and discuss the feasibility of targeting MAP3Ks for the treatment of virus-induced diseases.

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Section: Discussion and Perspectivesmentioning

confidence: 99%

Functions of MAP3Ks in antiviral immunity

et al. 2023

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“…Upon interaction with the T-cell and B-cell receptors, MAP4K1 triggers a phosphorylation cascade that includes the phosphorylation and then the degradation of the T-cell and B-cell effectors SLP76 and BLNK, respectively. MAP4K1 is also a negative regulator of the antiviral innate immune response by interacting with the ubiquitin ligase DTX4, which, in turn, ubiquitinates TBK1 for degradation [ 60 ] ( Figure 7 ). MAP4K1 activity and autophosphorylation then trigger its ubiquitination by the E3 ubiquitin ligase CUL7/fbxw8 and its degradation by the proteasome [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

A Degradation Motif in STAU1 Defines a Novel Family of Proteins Involved in Inflammation

Quesada

DesGroseillers²

2022

IJMS

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Cancer development is regulated by inflammation. Staufen1 (STAU1) is an RNA-binding protein whose expression level is critical in cancer cells as it is related to cell proliferation or cell death. STAU1 protein levels are downregulated during mitosis due to its degradation by the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C). In this paper, we map the molecular determinant involved in STAU1 degradation to amino acids 38–50, and by alanine scanning, we shorten the motif to F39PxPxxLxxxxL50 (FPL-motif). Mutation of the FPL-motif prevents STAU1 degradation by APC/C. Interestingly, a search in databases reveals that the FPL-motif is shared by 15 additional proteins, most of them being involved in inflammation. We show that one of these proteins, MAP4K1, is indeed degraded via the FPL-motif; however, it is not a target of APC/C. Using proximity labeling with STAU1, we identify TRIM25, an E3 ubiquitin ligase involved in the innate immune response and interferon production, as responsible for STAU1 and MAP4K1 degradation, dependent on the FPL-motif. These results are consistent with previous studies that linked STAU1 to cancer-induced inflammation and identified a novel degradation motif that likely coordinates a novel family of proteins involved in inflammation. Data are available via ProteomeXchange with the identifier PXD036675.

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“…HEK 293 cells were cultured in a 100 mm dish, 6 or 24-wells plates, and the indicated plasmids were transferred into the cells with calcium phosphate. Sendai viruses were used to infect cells for the indicated time after 12 h, cells were harvested for analysis after virus infection, and the reporter gene experiments were performed as previously described ( 27 , 28 ).…”

Section: Methodsmentioning

confidence: 99%

BAG6 negatively regulates the RLR signaling pathway by targeting VISA/MAVS

Huang

Xiao

et al. 2022

Front. Immunol.

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The virus-induced signaling adaptor protein VISA (also known as MAVS, ISP-1, Cardif) is a critical adaptor protein in the innate immune response to RNA virus infection. Upon viral infection, VISA self-aggregates to form a sizeable prion-like complex and recruits downstream signal components for signal transduction. Here, we discover that BAG6 (BCL2-associated athanogene 6, formerly BAT3 or Scythe) is an essential negative regulator in the RIG-I-like receptor signaling pathway. BAG6 inhibits the aggregation of VISA by promoting the K48-linked ubiquitination and specifically attenuates the recruitment of TRAF2 by VISA to inhibit RLR signaling. The aggregation of VISA and the interaction of VISA and TRAF2 are enhanced in BAG6-deficient cell lines after viral infection, resulting in the enhanced transcription level of downstream antiviral genes. Our research shows that BAG6 is a critical regulating factor in RIG-I/VISA-mediated innate immune response by targeting VISA.

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The Kinase MAP4K1 Inhibits Cytosolic RNA-Induced Antiviral Signaling by Promoting Proteasomal Degradation of TBK1/IKKε

Abstract: TANK-binding kinase 1 (TBK1)/IκB kinase-ε (IKKε) mediates robust production of type I interferons (IFN-I) and proinflammatory cytokines to restrict the spread of invading viruses. However, excessive or prolonged production of IFN-I is harmful to the host by causing autoimmune disorders.

Cited by 12 publications

References 55 publications

Functions of MAP3Ks in antiviral immunity

Functions of MAP3Ks in antiviral immunity

A Degradation Motif in STAU1 Defines a Novel Family of Proteins Involved in Inflammation

BAG6 negatively regulates the RLR signaling pathway by targeting VISA/MAVS

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