USP49 negatively regulates cellular antiviral responses via deconjugating K63-linked ubiquitination of MITA

Ye, Liya; Zhang, Qiang; Liuyu, Tianzi; Xu, Zhigao; Zhang, Meng-Xin; Luo, Min‐Hua; Zeng, Wen‐Bo; Zhu, Qing; Lin, Dandan; Zhong, Bo

doi:10.1371/journal.ppat.1007680

Cited by 44 publications

(36 citation statements)

References 67 publications

(93 reference statements)

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“…Eight-week-old male and female KP, KP7 or KL mice were intranasally injected with Ad-Cre followed by various Quantitative real-time PCR. These experiments were performed as previously described 54,55 . Total RNA was extracted from tumor or normal tissues or cells using TRIzol reagent (Invitrogen), and the first-strand cDNA was reversedtranscribed with All-in-One cDNA Synthesis SuperMix (Biotool).…”

Section: Discussionmentioning

confidence: 99%

CCL7 recruits cDC1 to promote antitumor immunity and facilitate checkpoint immunotherapy to non-small cell lung cancer

et al. 2020

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The efficacy of checkpoint immunotherapy to non-small cell lung cancer (NSCLC) largely depends on the tumor microenvironment (TME). Here, we demonstrate that CCL7 facilitates anti-PD-1 therapy for the KrasLSL−G12D/+Tp53fl/fl (KP) and the KrasLSL−G12D/+Lkb1fl/fl (KL) NSCLC mouse models by recruiting conventional DC 1 (cDC1) into the TME to promote T cell expansion. CCL7 exhibits high expression in NSCLC tumor tissues and is positively correlated with the infiltration of cDC1 in the TME and the overall survival of NSCLC patients. CCL7 deficiency impairs the infiltration of cDC1 in the TME and the subsequent expansion of CD8+ and CD4+ T cells in bronchial draining lymph nodes and TME, thereby promoting tumor development in the KP mouse model. Administration of CCL7 into lungs alone or in combination with anti-PD-1 significantly inhibits tumor development and prolongs the survival of KP and KL mice. These findings suggest that CCL7 potentially serves as a biomarker and adjuvant for checkpoint immunotherapy of NSCLC.

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Section: Discussionmentioning

confidence: 99%

CCL7 recruits cDC1 to promote antitumor immunity and facilitate checkpoint immunotherapy to non-small cell lung cancer

et al. 2020

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“…Recently, it has been shown that USP49 interacts with p53, dual-specificity protein phosphatases (DUSP), or FKBP51 in the nucleus, and consequently suppresses the ubiquitination of these proteins (Luo et al, 2017; Tu et al, 2018; Zhang et al, 2019). Regarding innate immunity, it can negatively regulate cellular antiviral responses via the deconjugation of K63-linked ubiquitin in STING, an adaptor protein that senses cytoplasmic DNA and is involved in various innate immune responses (Ye et al, 2019). Our data indicate that although USP49 is mainly distributed in the nucleus, it also exists in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

USP49 potently stabilizes APOBEC3G protein by removing ubiquitin and inhibits HIV-1 replication

Pan

Zheng

et al. 2019

eLife

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The antiviral activity of host factor apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G (APOBEC3G, A3G) and its degradation mediated by human immunodeficiency virus type 1 (HIV-1) Vif protein are important topics. Although accumulating evidence indicates the importance of deubiquitination enzymes (DUBs) in innate immunity, it is unknown if they participate in A3G stability. Here, we found that USP49 directly interacts with A3G and efficiently removes ubiquitin, consequently increasing A3G protein expression and significantly enhancing its anti-HIV-1 activity. Unexpectedly, A3G degradation was also mediated by a Vif- and cullin-ring-independent pathway, which was effectively counteracted by USP49. Furthermore, clinical data suggested that USP49 is correlated with A3G protein expression and hypermutations in Vif-positive proviruses, and inversely with the intact provirus ratio in the HIV-1 latent reservoir. Our studies demonstrated a mechanism to effectively stabilize A3G expression, which could comprise a target to control HIV-1 infection and eradicate the latent reservoir.

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“…The plasmid encoding GST-Ub-Tandem Ubiquitin Binding Entity (TUBE) was previously described and kindly provided by Dr. M. Gyrd-Hansen (University of Oxford, Oxford, UK; Fiil et al, 2013 ). GST-TUBE was expressed in Escherichia coli (DE3) and purified with a GST column as previously described ( Ye et al, 2019 ; Zhao et al, 2018 ). To analyze ubiquitinated KPNA2 or IRF3, GST-TUBE was incubated with cell lysates and pulled down by GST beads.…”

Section: Methodsmentioning

confidence: 99%

USP22 promotes IRF3 nuclear translocation and antiviral responses by deubiquitinating the importin protein KPNA2

Cai

Zhang

Tang

et al. 2020

Journal of Experimental Medicine

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USP22 is a cytoplasmic and nuclear deubiquitinating enzyme, and the functions of cytoplasmic USP22 are unclear. Here, we discovered that cytoplasmic USP22 promoted nuclear translocation of IRF3 by deubiquitianting and stabilizing KPNA2 after viral infection. Viral infection induced USP22-IRF3 association in the cytoplasm in a KPNA2-depedent manner, and knockdown or knockout of USP22 or KPNA2 impaired IRF3 nuclear translocation and expression of downstream genes after viral infection. Consistently, Cre-ER Usp22fl/fl or Lyz2-Cre Usp22fl/fl mice produced decreased levels of type I IFNs after viral infection and exhibited increased susceptibility to lethal viral infection compared with the respective control littermates. Mechanistically, USP22 deubiquitinated and stabilized KPNA2 after viral infection to facilitate efficient nuclear translocation of IRF3. Reconstitution of KPNA2 into USP22 knockout cells restored virus-triggered nuclear translocation of IRF3 and cellular antiviral responses. These findings define a previously unknown function of cytoplasmic USP22 and establish a mechanistic link between USP22 and IRF3 nuclear translocation that expands potential therapeutic strategies for infectious diseases.

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USP49 negatively regulates cellular antiviral responses via deconjugating K63-linked ubiquitination of MITA

Cited by 44 publications

References 67 publications

CCL7 recruits cDC1 to promote antitumor immunity and facilitate checkpoint immunotherapy to non-small cell lung cancer

CCL7 recruits cDC1 to promote antitumor immunity and facilitate checkpoint immunotherapy to non-small cell lung cancer

USP49 potently stabilizes APOBEC3G protein by removing ubiquitin and inhibits HIV-1 replication

USP22 promotes IRF3 nuclear translocation and antiviral responses by deubiquitinating the importin protein KPNA2

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