The Human Cytomegalovirus pUL145 Isoforms Act as Viral DDB1-Cullin-Associated Factors to Instruct Host Protein Degradation to Impede Innate Immunity

Le‐Trilling, Vu Thuy Khanh; Becker, Tanja; Nachshon, Aharon; Stern-Ginossar, Noam; Schöler, Lara; Voigt, Sebastian; Hengel, Hartmut; Trilling, Mirko

doi:10.1016/j.celrep.2020.01.070

Cited by 35 publications

(45 citation statements)

References 63 publications

(57 reference statements)

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“…Similarly, certain human cytomegalovirus strains encode pUL145. pUL145 was recently demonstrated to simultaneously interact with STAT2 and CRL4 adaptor DDB1 and thereby targets STAT2 for ubiquitination and degradation by CRL4 [199]. MLN4924 treatment restored STAT2 expression in infected cells and elicited antiviral activity [180,200].…”

Section: Neddylation and Viral Infectionmentioning

confidence: 99%

Diverse and pivotal roles of neddylation in metabolism and immunity

Zou

Zhang

2020

The FEBS Journal

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Neddylation is one type of protein post-translational modification by conjugating a ubiquitin-like protein neural precursor cell-expressed developmentally downregulated protein 8 to substrate proteins via a cascade involving E1, E2, and E3 enzymes. The best-characterized substrates of neddylation are cullins, essential components of cullin-RING E3 ubiquitinligase complexes. The discovery of noncullin neddylation targets indicates that neddylation may have diverse biological functions. Indeed, neddylation has been implicated in various cellular processes including cell cycle progression, metabolism, immunity, and tumorigenesis. Here, we summarized the reported neddylation substrates and also discuss the functions of neddylation in the immune system and metabolism.

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Section: Neddylation and Viral Infectionmentioning

confidence: 99%

Diverse and pivotal roles of neddylation in metabolism and immunity

Zou

Zhang

2020

The FEBS Journal

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“…To ascertain which ULb' gene(s) were responsible for the observed phenotype, we utilized an array of block and single-gene deletion mutants generated on the BAC2 background (38,48) ( Fig. 1B).…”

Section: Ul147a-deficient Hcmv Mutants Are Impaired In Mica*008 Downrmentioning

confidence: 99%

“…AD169VarS and AD169VarL were isolated and cloned into BAC2 and BAC20 as previously described (55). BAC2-generated ULb' block deletion mutants were previously described (48).…”

Section: Other Examples Of Multiple Hcmv Immunoevasins Targeting a Simentioning

confidence: 99%

“…It is encoded in the ULb' region located at the right end of the unique long HCMV genomic segment. This 13-15 kbp region encompassing the UL133-UL150 genes is known to encode multiple immune evasion factors (32,33,50,38,39,(44)(45)(46)(47)(48)(49) and is present in clinical HCMV isolates but is frequently lost during serial passaging in fibroblast cell culture (7,42,(51)(52)(53)(54). However, UL147A is highly conserved in clinical isolates with a maximum of 6-7% sequence variability (41).…”

Section: Introductionmentioning

confidence: 99%

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The human cytomegalovirus protein UL147A downregulates the most prevalent MICA allele: MICA*008, to evade NK cell-mediated killing

Seidel¹,

Dassa²,

Oiknine‐Djian

et al. 2020

Preprint

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Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells without prior sensitization. NK cell activity is regulated by signals received from activating and inhibitory receptors. One pivotal activating NK receptor is NKG2D, which binds a family of eight ligands, including the major histocompatibility complex (MHC) class I-related chain A (MICA). Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus causing morbidity and mortality in immunosuppressed patients and congenitally infected infants. HCMV encodes multiple antagonists of NK cell activation, including many mechanisms targeting MICA. However, only one of these mechanisms counters the most prevalent MICA allele, MICA*008. Here, we discover that a hitherto uncharacterized HCMV protein, UL147A, specifically targets MICA*008 to proteasomal degradation, thus hindering the elimination of HCMV-infected cells by NK cells. Mechanistic analyses disclose that the non-canonical GPI anchoring pathway of immature MICA*008 constitutes the determinant of UL147A specificity for this MICA allele. These findings advance our understanding of the complex and rapidly evolving HCMV immune evasion mechanisms, which may facilitate the development of antiviral drugs and vaccines.

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“…Virus mutants lacking these immune evasins are replication competent but highly attenuated in vivo [28]. The protein pM27 mediates STAT2 degradation in the MCMV context, while human CMV (HCMV) encodes the protein pUL145 which acts as a functional analog of pM27 [29]. The proteins pM27 and pUL145 share a functionally relevant H‐box motif present in viral and cellular DDB1 Cullin‐associated factors.…”

Section: Introductionmentioning

confidence: 99%

Prophylactic and therapeutic HBV vaccination by an HBs‐expressing cytomegalovirus vector lacking an interferon antagonist in mice

et al. 2020

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Cytomegalovirus (CMV)‐based vaccines show promising effects against chronic infections in nonhuman primates. Therefore, we examined the potential of hepatitis B virus (HBV) vaccines based on mouse CMV (MCMV) vectors expressing the small HBsAg. Immunological consequences of vaccine virus attenuation were addressed by either replacing the dispensable gene m157 (“MCMV‐HBsȍ) or the gene M27 (“ΔM27‐HBs”), the latter encodes a potent IFN antagonist targeting the transcription factor STAT2. M27 was chosen, since human CMV encodes an analogous gene product, which also induced proteasomal STAT2 degradation by exploiting Cullin RING ubiquitin ligases. Vaccinated mice were challenged with HBV through hydrodynamic injection. MCMV‐HBs and ΔM27‐HBs vaccination achieved accelerated HBV clearance in serum and liver as well as robust HBV‐specific CD8+ T‐cell responses. When we explored the therapeutic potential of MCMV‐based vaccines, especially the combination of ΔM27‐HBs prime and DNA boost vaccination resulted in increased intrahepatic HBs‐specific CD8+ T‐cell responses and HBV clearance in persistently infected mice. Our results demonstrated that vaccines based on a replication competent MCMV attenuated through the deletion of an IFN antagonist targeting STAT2 elicit robust anti‐HBV immune responses and mediate HBV clearance in mice in prophylactic and therapeutic immunization regimes.

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The Human Cytomegalovirus pUL145 Isoforms Act as Viral DDB1-Cullin-Associated Factors to Instruct Host Protein Degradation to Impede Innate Immunity

Cited by 35 publications

References 63 publications

Diverse and pivotal roles of neddylation in metabolism and immunity

Diverse and pivotal roles of neddylation in metabolism and immunity

The human cytomegalovirus protein UL147A downregulates the most prevalent MICA allele: MICA*008, to evade NK cell-mediated killing

Prophylactic and therapeutic HBV vaccination by an HBs‐expressing cytomegalovirus vector lacking an interferon antagonist in mice

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