Viral Inhibition of PRR-Mediated Innate Immune Response: Learning from KSHV Evasion Strategies

Lee, Hye‐Ra; Choi, Un Yung; Hwang, Sungwoo; Kim, Stephanie; Jung, Jae U.

doi:10.14348/molcells.2016.0232

Cited by 17 publications

(17 citation statements)

References 77 publications

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“…In this study, it was verified that the ATG10 mutants without Cys 44 and Cys 135 also elevated the levels of il28a /IL28a, ifr-3 /IRF-3, and irf-7 /IRF-7. IRF-3 and IRF-7 could induce IFNs expression as interferon regulatory factors ( 46 , 47 ) by nuclear-translocation upon virus infection ( 48 ). In this study, the nuclear translocation and nuclear–cytoplasmic fractionation assays indicated that the ATG10 mutant proteins surprisingly translocated into the nucleus much like the ATG10S protein, but ATG10 and ATG10 ΔM43 did not.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Autophagy-Related 10 Protein on HCV Replication and Autophagy Flux Are Mediated by Its Cysteine44 and Cysteine135

Zhang

Peng

et al. 2018

Front. Immunol.

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Autophagy-related 10 (ATG10) is essential for autophagy since it promotes ATG5-ATG12 complex formation. Our previous study found that there are two isoforms of the ATG10 protein, ATG10 (a longer one) and ATG10S, which have identical sequences except an absence of a 36-amino acid fragment (peptide B) in ATG10S, yet exhibit distinct effects on HCV genome replication. Here, we report the existence of two amino acids, cysteine at residue 44 and 135 (Cys44 and Cys135, respectively), in ATG10 being related to differential effects of ATG10 on HCV replication and autophagy flux. Through a series of ATG10 mutation experiments and protein modeling prediction, we found that Cys44 was involved in the dual role of the two isoforms of ATG10 protein on HCV replication and autophagy flux, and that Cys135 plays similar roles as Cys44, but the disulfide bond of Cys44-Cys135 was not verified in the ATG10 protein. Further analyses by full HCV virion infection confirmed the roles of -SH of Cys44 and Cys135 on HCV replication. ATG10 with deleted or mutated Cys44 and/or Cys135 could activate expression of innate immunity-related genes, including il28a, irf-3, irf-7, and promote complete autophagy by driving autophagosomes to interact with lysosomes via IL28A-mediation. Subcellular localization assay and chromatin immunoprecipitation assay showed that ATG10 with the sulfydryl deletion or substitution of Cys44 and Cys135 could translocate into the nucleus and bind to promoter of IL28A gene; the results indicated that ATG10 with Cys44 and/or Cys135 absence might act as transcriptional factors to trigger the expression of anti-HCV immunological genes, too. In conclusion, our findings provide important information for understanding the differential roles on HCV replication and autophagy flux between ATG10 and ATG10S, and how the structure-function relationship of ATG10 transformed by a single -SH group loss on Cys44 and Cys135 in ATG10 protein, which may be a new target against HCV replication.

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Section: Discussionmentioning

confidence: 99%

Differential Effects of Autophagy-Related 10 Protein on HCV Replication and Autophagy Flux Are Mediated by Its Cysteine44 and Cysteine135

Zhang

Peng

et al. 2018

Front. Immunol.

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“…Hence, there exists a need for the viruses to manipulate the host immune surveillance mechanism to facilitate their propagation efficiently [1,8]. Because of this, KSHV encodes for various immunomodulatory proteins, including four vIRFs (vIRF1 to 4) that are homologous to cellular IRFs [17].…”

Section: Resultsmentioning

confidence: 99%

“…These IFNs are upregulated by interferon regulatory factors (IRFs), which serve as transcriptional factors [1]. Among them, IRF3 and IRF7 especially act as direct transducers of viral-mediated type I IFN gene induction.…”

Section: Introductionmentioning

confidence: 99%

KSHV-encoded viral interferon regulatory factor 4 (vIRF4) interacts with IRF7 and inhibits interferon alpha production

Hwang

Kim

Jung

et al. 2017

Biochemical and Biophysical Research Communications

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Before an infection can be completely established, the host immediately turns on the innate immune system through activating the interferon (IFN)-mediated antiviral pathway. Kaposi’s sarcoma-associated herpesvirus (KSHV) utilizes a unique antagonistic mechanism of type I IFN-mediated host antiviral immunity by incorporating four viral interferon regulatory factors (vIRF1-4). Herein, we characterized novel immune evasion strategies of vIRF4 to inhibit the IRF7-mediated IFN-α production. KSHV vIRF4 specifically interacts with IRF7, resulting in inhibition of IRF7 dimerization and ultimately suppresses IRF7-mediated activation of type I IFN. These results suggest that each of the KSHV vIRFs, including vIRF4, subvert IFN-mediated anti-viral response via different mechanisms. Therefore, it is indicated that KSHV vIRFs are indeed a crucial immunomodulatory component of their life cycles.

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“…The KSHV genome encodes four types of viral interferon regulatory factors (vIRFs), vIRF1 to vIRF4, which are homologous to cellular IRFs, which are clustered within one genomic locus ( 18 – 20 ). Although all vIRFs inhibit both host interferon response and control cellular growth, differences in their activation characteristics result in distinct immune evasion strategies.…”

Section: Introductionmentioning

confidence: 99%

“…This enables efficient lifelong persistence and facilitates the development of KSHV-associated malignancy. Expression of vIRF3 is required for continuous proliferation of PEL cells ( 21 ) and causes dramatic changes in critical host pathways such as apoptosis, cell cycle, antiviral immune response, and tumorigenesis ( 9 , 18 – 20 ). It was previously shown that vIRF3 (also referred to as LANA-2) is constitutively expressed in B cell lymphotropic diseases, PEL, and MCD but not in KS tumors ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

Deregulation of HDAC5 by Viral Interferon Regulatory Factor 3 Plays an Essential Role in Kaposi's Sarcoma-Associated Herpesvirus-Induced Lymphangiogenesis

Lee

Choi

et al. 2018

mBio

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Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent for Kaposi’s sarcoma (KS), which is one of the most common HIV-associated neoplasms. The endothelium is the thin layer of squamous cells where vascular blood endothelial cells (BECs) line the interior surface of blood vessels and lymphatic endothelial cells (LECs) are in direct contact with lymphatic vessels. The KS lesions contain a prominent compartment of neoplastic spindle morphology cells that are closely related to LECs. Furthermore, while KSHV can infect both LECs and BECs in vitro, its infection activates genetic programming related to lymphatic endothelial cell fate, suggesting that lymphangiogenic pathways are involved in KSHV infection and malignancy. Here, we report for the first time that viral interferon regulatory factor 3 (vIRF3) is readily detected in over 40% of KS lesions and that vIRF3 functions as a proangiogenic factor, inducing hypersprouting formation and abnormal growth in a LEC-specific manner. Mass spectrometry analysis revealed that vIRF3 interacted with histone deacetylase 5 (HDAC5), which is a signal-responsive regulator for vascular homeostasis. This interaction blocked the phosphorylation-dependent cytosolic translocation of HDAC5 and ultimately altered global gene expression in LECs but not in BECs. Consequently, vIRF3 robustly induced spindle morphology and hypersprouting formation of LECs but not BECs. Finally, KSHV infection led to the hypersprouting formation of LECs, whereas infection with a ΔvIRF3 mutant did not do so. Collectively, our data indicate that vIRF3 alters global gene expression and induces a hypersprouting formation in an HDAC5-binding-dependent and LEC-specific manner, ultimately contributing to KSHV-associated pathogenesis.

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Viral Inhibition of PRR-Mediated Innate Immune Response: Learning from KSHV Evasion Strategies

Cited by 17 publications

References 77 publications

Differential Effects of Autophagy-Related 10 Protein on HCV Replication and Autophagy Flux Are Mediated by Its Cysteine44 and Cysteine135

Differential Effects of Autophagy-Related 10 Protein on HCV Replication and Autophagy Flux Are Mediated by Its Cysteine44 and Cysteine135

KSHV-encoded viral interferon regulatory factor 4 (vIRF4) interacts with IRF7 and inhibits interferon alpha production

Deregulation of HDAC5 by Viral Interferon Regulatory Factor 3 Plays an Essential Role in Kaposi's Sarcoma-Associated Herpesvirus-Induced Lymphangiogenesis

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