Crystal Structure of Human Herpesvirus 6B Tegument Protein U14

Wang, Bochao; Nishimura, Mitsuhiro; Tang, Huiping; Kawabata, Akiko; Mahmoud, Nora F.; Khanlari, Zahra; Hamada, Daizo; Tsuruta, Hiroki; Mori, Yasuko

doi:10.1371/journal.ppat.1005594

Cited by 13 publications

(31 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, we investigated whether the HCMV homologue of M35, UL35, can likewise modulate PRR signaling. Although M35 and UL35 share only 25% amino acid identity, structure remodeling using the human herpesvirus 6B (HHV-6B) homologue U14 as the template [16] predicted a high similarity for their three-dimensional protein structure. The UL35 open reading frame (ORF) codes for the 75 kDa ppUL35 phosphoprotein (herein referred to as UL35) which was identified as a minor tegument component of HCMV [17].…”

Section: Introductionmentioning

confidence: 99%

The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription

et al. 2020

View full text Add to dashboard Cite

The rapid activation of pattern recognition receptor (PRR)-mediated type I interferon (IFN) signaling is crucial for the host response to infection. In turn, human cytomegalovirus (HCMV) must evade this potent response to establish life-long infection. Here, we reveal that the HCMV tegument protein UL35 antagonizes the activation of type I IFN transcription downstream of the DNA and RNA sensors cGAS and RIG-I, respectively. We show that ectopic expression of UL35 diminishes the type I IFN response, while infection with a recombinant HCMV lacking UL35 induces an elevated type I IFN response compared to wildtype HCMV. With a series of luciferase reporter assays and the analysis of signaling kinetics upon HCMV infection, we observed that UL35 downmodulates PRR signaling at the level of the key signaling factor TANK-binding kinase 1 (TBK1). Finally, we demonstrate that UL35 and TBK1 co-immunoprecipitate when co-expressed in HEK293T cells. In addition, we show that a previously reported cellular binding partner of UL35, O-GlcNAc transferase (OGT), post-translationally GlcNAcylates UL35, but that this modification is not required for the antagonizing effect of UL35 on PRR signaling. In summary, we have identified UL35 as the first HCMV protein to antagonize the type I IFN response at the level of TBK1, thereby enriching our understanding of how this important herpesvirus escapes host immune responses.

show abstract

Section: Introductionmentioning

confidence: 99%

The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Difficulties in cultivating HHV-6B have prevented high-resolution structural studies and limited our understanding of its assembly. Despite recent progress in our understanding of representative members of all three subfamilies of the Herpesviridae 4–8 , including fellow β-herpesvirus subfamily members such as human 8 and murine 9 cytomegaloviruses, the only available structures for HHV-6 are a very low-resolution (30 Å) capsid structure, generated from ~ 30 particles 10 , and a crystal structure for pU14 (a putative tegument protein with unknown functions) 11 . However, human cytomegalovirus (HCMV) has its structure established at a resolution of 3.9 Å; it shows that pp150, a β-herpesvirus subfamily-specific tegument protein, forms a “△”-shaped group-of-three structure on each of the 320 triplexes in a capsid, leading to a net that encloses the capsid.…”

Section: Introductionmentioning

confidence: 99%

Atomic structure of the human herpesvirus 6B capsid and capsid-associated tegument complexes

Zhang

Liu

et al. 2019

Nat Commun

View full text Add to dashboard Cite

Human herpesvirus 6B (HHV-6B) belongs to the β-herpesvirus subfamily of the Herpesviridae. To understand capsid assembly and capsid-tegument interactions, here we report atomic structures of HHV-6B capsid and capsid-associated tegument complex (CATC) obtained by cryoEM and sub-particle reconstruction. Compared to other β-herpesviruses, HHV-6B exhibits high similarity in capsid structure but organizational differences in its CATC (pU11 tetramer). 180 “VΛ”-shaped CATCs are observed in HHV-6B, distinguishing from the 255 “Λ”-shaped dimeric CATCs observed in murine cytomegalovirus and the 310 “Δ”-shaped CATCs in human cytomegalovirus. This trend in CATC quantity correlates with the increasing genomes sizes of these β-herpesviruses. Incompatible distances revealed by the atomic structures rationalize the lack of CATC’s binding to triplexes Ta, Tc, and Tf in HHV-6B. Our results offer insights into HHV-6B capsid assembly and the roles of its tegument proteins, including not only the β-herpesvirus-specific pU11 and pU14, but also those conserved across all subfamilies of Herpesviridae.

show abstract

“…pUL25 orthologous proteins can be found in other members of the Betaherpesvirus family (41,42). The murine orthologue M25 has recently been investigated (41).…”

Section: Discussionmentioning

confidence: 99%

The Abundant Tegument Protein pUL25 of Human Cytomegalovirus Prevents Proteasomal Degradation of pUL26 and Supports Its Suppression of ISGylation

Zimmermann

Büscher

Krauter

et al. 2018

J Virol

View full text Add to dashboard Cite

The tegument of human cytomegalovirus (HCMV) virions contains proteins that interfere with both the intrinsic and the innate immunity. One protein with a thus far unknown function is pUL25. The deletion of pUL25 in a viral mutant (Towne-ΔUL25) had no impact on the release of virions and subviral dense bodies or on virion morphogenesis. Proteomic analyses showed few alterations in the overall protein composition of extracellular particles. A surprising result, however, was the almost complete absence of pUL26 in virions and dense bodies of Towne-ΔUL25 and a reduction of the large isoform pUL26-p27 in mutant virus-infected cells. pUL26 had been shown to inhibit protein conjugation with the interferon-stimulated gene 15 protein (ISG15), thereby supporting HCMV replication. To test for a functional relationship between pUL25 and pUL26, we addressed the steady-state levels of pUL26 and found them to be reduced in Towne-ΔUL25-infected cells. Coimmunoprecipitation experiments proved an interaction between pUL25 and pUL26. Surprisingly, the overall protein ISGylation was enhanced in Towne-ΔUL25-infected cells, thus mimicking the phenotype of a pUL26-deleted HCMV mutant. The functional relevance of this was confirmed by showing that the replication of Towne-ΔUL25 was more sensitive to beta interferon. The increase of protein ISGylation was also seen in cells infected with a mutant lacking the tegument protein pp65. Upon retesting, we found that pUL26 degradation was also increased when pp65 was unavailable. Our experiments show that both pUL25 and pp65 regulate pUL26 degradation and the pUL26-dependent reduction of ISGylation and add pUL25 as another HCMV tegument protein that interferes with the intrinsic immunity of the host cell.IMPORTANCE Human cytomegalovirus (HCMV) expresses a number of tegument proteins that interfere with the intrinsic and the innate defense mechanisms of the cell. Initial induction of the interferon-stimulated gene 15 protein (ISG15) and conjugation of proteins with ISG15 (ISGylation) by HCMV infection are subsequently attenuated by the expression of the viral IE1, pUL50, and pUL26 proteins. This study adds pUL25 as another factor that contributes to suppression of ISGylation. The tegument protein interacts with pUL26 and prevents its degradation by the proteasome. By doing this, it supports its restrictive influence on ISGylation. In addition, a lack of pUL25 enhances the levels of free ISG15, indicating that the tegument protein may interfere with the interferon response on levels other than interacting with pUL26. Knowledge obtained in this study widens our understanding of HCMV immune evasion and may also provide a new avenue for the use of pUL25-negative strains for vaccine production.

show abstract

Crystal Structure of Human Herpesvirus 6B Tegument Protein U14

Cited by 13 publications

References 50 publications

The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription

The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription

Atomic structure of the human herpesvirus 6B capsid and capsid-associated tegument complexes

The Abundant Tegument Protein pUL25 of Human Cytomegalovirus Prevents Proteasomal Degradation of pUL26 and Supports Its Suppression of ISGylation

Contact Info

Product

Resources

About