Novel virus-associated proteins encoded by UL112–113 of human cytomegalovirus

Wang, Shang‐Kwei; Hu, Cheng-Hui; Lu, Miao-Chan; Duh, Chang‐Yih; Liao, Pao‐Chi; Tyan, Yu‐Chang

doi:10.1099/vir.0.013037-0

Cited by 7 publications

(8 citation statements)

References 39 publications

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“…2b, lanes 2, 4, 6 and 8). The p34c protein is a new finding in this study, whereas p38 was identified by proteomic analyses in our previous study (Wang et al, 2009). Our results suggest that the maitotoxin-induced protease modulates the proteolysis of UL112-113 proteins.…”

Section: Calcium Influx Elicits Proteolysis Of the Ul112-113 Proteinssupporting

confidence: 56%

“…Previously, we showed that the UL112-113 region produces eight cognate proteins, p20, p26, p28, p34, p38, p43, p50 and p84 (Wang et al, 2009). The p34 protein is translated from the un-spliced transcript, whereas alternative splicing yields p43, p50 and p84.…”

Section: Introductionmentioning

confidence: 99%

“…The p34, p43, p50 and p84 proteins share the exon 1 sequence, which encodes 252 N-terminal amino acids. The p43, p50 and p84 proteins contain amino acids from exon 2, whereas their C-terminal sequences are each derived from unique exons (Wang et al, 2009;Wright & Spector, 1989). The additional proteins p20, p26, p28 and p38 also contain UL112 exon 1.…”

Section: Introductionmentioning

confidence: 99%

“…The additional proteins p20, p26, p28 and p38 also contain UL112 exon 1. Moreover, p20, p26 and p28 are selectively packaged into viral particles (Wang et al, 2009). Because the N-termini of UL112-113 proteins likely bind to DNA, are required for self-interaction and mediate the recruitment of replication complexes (Kim & Ahn, 2010;Park et al, 2006), we reasoned that the proteolytic processing of UL112-113 proteins merited further investigation.…”

Section: Introductionmentioning

confidence: 99%

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Calpains mediate the proteolytic modification of human cytomegalovirus UL112-113 proteins

Wang

Jiang

Lin

et al. 2015

Journal of General Virology

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The human cytomegalovirus (HCMV) UL112-113 gene is implicated in lytic viral replication. The UL112-113 proteins p34, p43, p50 and p84 are expressed via alternative splicing. However, the mechanism for the generation of three additional virus-associated proteins (p20, p26 and p28), which share the UL112 reading frame, remains unknown. Bioinformatic analyses indicated that p34, p43, p50 and p84 contain potential PEST-like degradation motifs. In this study, inhibitors of calpains, lysosomes and proteasomes reduced p20, p26 and p28 levels in virus-infected cells, suggesting the involvement of proteolytic modification. Moreover, maitotoxin, which increases intracellular calcium levels and activates calpain activity, induced the intracellular proteolysis of p34 into p20, p26 and p28 and the cleavage of p43, p50 and p84 into p38 and a novel protein, p34c. Proteolytic assays further indicated that p34, p43, p50 and p84 were substrates of calpain-1 and calpain-2 and that they generated proteolytic products that corresponded to those detected during the HCMV infectious period. Furthermore, substitution mutations in the putative calpain cleavage sites of p34 reduced accumulation of proteolytic products. The knockdown of endogenous calpain-1 and calpain-2 by RNA interference reduced accumulation of p20, p26 and p28 and concurrently increased levels of nascent p43, p50 and p84 during the infectious cycle. Intriguingly, calpain depletion enhanced viral genome synthesis. Moreover, HCMV-permissive cells that stably expressed p20, p26 or p28 exhibited reduced viral genome synthesis and mature virus production. Our findings suggest that cognate UL112-113 proteins derived from calpaincatalysed proteolysis are involved in the HCMV replication process.

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Section: Calcium Influx Elicits Proteolysis Of the Ul112-113 Proteinssupporting

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Calpains mediate the proteolytic modification of human cytomegalovirus UL112-113 proteins

Wang

Jiang

Lin

et al. 2015

Journal of General Virology

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“…A polyclonal antibody (Ab) against UL76 was raised in this study via immunization of mice using oligopeptide amino acids 244 to 267 (CRAHGPGAQTVSASGAQGSGSQGAD). Polyclonal rabbit anti-UL112 was described previously (39). Monoclonal mouse anti-myc tag (clone 9B11), mouse anti-hemagglutinin (HA) tag (clone 6E2), anti-ubiquitin (clone P4D1), polyclonal rabbit anti-K48 linkage-specific polyubiquitin, and monoclonal rabbit anti-S5a (D17E4) antibodies were obtained from Cell Signaling.…”

Section: Cells and Virusesmentioning

confidence: 99%

Human Cytomegalovirus UL76 Elicits Novel Aggresome Formation via Interaction with S5a of the Ubiquitin Proteasome System

Lin

Jiang

Wang

et al. 2013

J Virol

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dHCMV UL76 is a member of a conserved Herpesviridae protein family (Herpes_UL24) that is involved in viral production, latency, and reactivation. UL76 presents as globular aggresomes in the nuclei of transiently transfected cells. Bioinformatic analyses predict that UL76 has a propensity for aggregation and targets cellular proteins implicated in protein folding and ubiquitinproteasome systems (UPS). Furthermore, fluorescence recovery after photobleaching experiments suggests that UL76 reduces protein mobility in the aggresome, which indicates that UL76 elicits the aggregation of misfolded proteins. Moreover, in the absence of other viral proteins, UL76 interacts with S5a, which is a major receptor of polyubiquitinated proteins for UPS proteolysis via its conserved region and the von Willebrand factor type A (VWA) domain of S5a. We demonstrate that UL76 sequesters polyubiquitinated proteins and S5a to nuclear aggresomes in biological proximity. After knockdown of endogenous S5a by RNA interference techniques, the UL76 level was only minimally affected in transiently expressing cells. However, a significant reduction in the number of cells containing UL76 nuclear aggresomes was observed, which suggests that S5a may play a key role in aggresome formation. Moreover, we show that UL76 interacts with S5a in the late phase of viral infection and that knockdown of S5a hinders the development of both the replication compartment and the aggresome. In this study, we demonstrate that UL76 induces a novel nuclear aggresome, likely by subverting S5a of the UPS. Given that UL76 belongs to a conserved family, this underlying mechanism may be shared by all members of the Herpesviridae.

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Quantitative Temporal Viromics: An Approach to Investigate Host-Pathogen Interaction

Weekes

Tomašec

Huttlin

et al. 2014

Cell

387

541

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SummaryA systematic quantitative analysis of temporal changes in host and viral proteins throughout the course of a productive infection could provide dynamic insights into virus-host interaction. We developed a proteomic technique called “quantitative temporal viromics” (QTV), which employs multiplexed tandem-mass-tag-based mass spectrometry. Human cytomegalovirus (HCMV) is not only an important pathogen but a paradigm of viral immune evasion. QTV detailed how HCMV orchestrates the expression of >8,000 cellular proteins, including 1,200 cell-surface proteins to manipulate signaling pathways and counterintrinsic, innate, and adaptive immune defenses. QTV predicted natural killer and T cell ligands, as well as 29 viral proteins present at the cell surface, potential therapeutic targets. Temporal profiles of >80% of HCMV canonical genes and 14 noncanonical HCMV open reading frames were defined. QTV is a powerful method that can yield important insights into viral infection and is applicable to any virus with a robust in vitro model.PaperClip

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Novel virus-associated proteins encoded by UL112–113 of human cytomegalovirus

Cited by 7 publications

References 39 publications

Calpains mediate the proteolytic modification of human cytomegalovirus UL112-113 proteins

Calpains mediate the proteolytic modification of human cytomegalovirus UL112-113 proteins

Human Cytomegalovirus UL76 Elicits Novel Aggresome Formation via Interaction with S5a of the Ubiquitin Proteasome System

Quantitative Temporal Viromics: An Approach to Investigate Host-Pathogen Interaction

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