Human Cytomegalovirus Regulates Surface Expression of the Viral Protein UL18 by Means of Two Motifs Present in the Cytoplasmic Tail

Maffei, Massimo; Ghiotto, Fabio; Occhino, Marzia; Bono, Marı́a Rosa; Santanna, Amleto De; Battini, Lorenzo; Gusella, G. Luca; Fais, Franco; Bruno, Silvia; Ciccone, Ermanno

doi:10.4049/jimmunol.180.2.969

Cited by 8 publications

(10 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite the observed ER/cis-Golgi apparatus localization of tagged UL142, it was possible that the subcellular localization of UL142 might be altered in the presence of other proteins expressed during HCMV infection. This phenomenon was recently described for UL18, which localizes predominantly to the ER and cis-Golgi apparatus when expressed in isolation (32). However, we observed that GFP-UL142 transiently expressed during HCMV infection remained localized to the ER.…”

Section: Discussioncontrasting

confidence: 51%

NKG2D Ligand MICA Is Retained in thecis-Golgi Apparatus by Human Cytomegalovirus Protein UL142

Ashiru¹,

Bennett²,

Boyle

et al. 2009

J Virol

101

View full text Add to dashboard Cite

Human cytomegalovirus (HCMV) evades T-cell recognition by down-regulating expression of major histocompatibility complex (MHC) class I and II molecules on the surfaces of infected cells. Contrary to the "missing-self" hypothesis, HCMV-infected cells are refractory to lysis by natural killer (NK) cells. Inhibition of NK cell function is mediated by a number of HCMV immune evasion molecules, which operate by delivering inhibitory signals to NK cells and preventing engagement of activating ligands. One such molecule is UL142, which is an MHC class I-related glycoprotein encoded by clinical isolates and low-passage-number strains of HCMV. UL142 is known to down-modulate surface expression of MHC class I-related chain A (MICA), which is a ligand of the activating NK receptor NKG2D. However, the mechanism by which UL142 interferes with MICA is unknown. Here, we show that UL142 localizes predominantly to the endoplasmic reticulum (ER) and cis-Golgi apparatus. The transmembrane domain of UL142 mediates its ER localization, while we propose that the UL142 luminal domain is involved in its cis-Golgi localization. We also confirm that UL142 downmodulates surface expression of full-length MICA alleles while having no effect on the truncated allele MICA*008. However, we demonstrate for the first time that UL142 retains full-length MICA alleles in the cis-Golgi apparatus. In addition, we propose that UL142 interacts with nascent MICA en route to the cell surface but not mature MICA at the cell surface. Our data also demonstrate that the UL142 luminal and transmembrane domains are involved in recognition and intracellular sequestration of full-length MICA alleles.Human cytomegalovirus (HCMV), a member of the Herpesviridae family, is a ubiquitous human pathogen with seroprevalence ranging between 50 to 100% worldwide (46). Severe morbidity and mortality are associated with HCMV infection in individuals that are immunocompromised or immunologically immature (25), and the severity of HCMV disease in immunocompromised individuals correlates with the level of immune suppression. However, HCMV infection in healthy immunocompetent individuals is usually asymptomatic/subclinical (25). Like all herpesviruses, HCMV establishes lifelong latent infection, HCMV residues, in hematopoietic cells of the myeloid lineage (45). Thus, following primary infection, HCMV persists in the host despite a robust humoral and cellmediated immune response.HCMV down-modulates surface expression of host major histocompatibility complex (MHC) class I molecules in order to evade T-cell recognition (5, 7, 24), but in doing so, the virus risks natural killer (NK) cell activation due to the lack of inhibitory receptor signaling (30). However, there is now ample evidence that HCMV evades NK cell-mediated lysis by a variety of different mechanisms (58). These include the expression of molecules that engage inhibitory NK receptors, as well as the down-modulation of ligands for activating NK receptors.The HCMV UL40 open reading frame encodes a nonameric peptide that ...

show abstract

Section: Discussioncontrasting

confidence: 51%

NKG2D Ligand MICA Is Retained in thecis-Golgi Apparatus by Human Cytomegalovirus Protein UL142

Ashiru¹,

Bennett²,

Boyle

et al. 2009

J Virol

101

View full text Add to dashboard Cite

show abstract

“…We observe identical localization of the wild-type (non-epitope-tagged) pUL138 in infection using our polyclonal antiserum to pUL138, indicating that the Myc epitope tag has not altered pUL138 localization. Localization of pUL138 to the Golgi apparatus is consistent with the presence of multiple Golgi localization motifs in the protein sequence, including three tyrosine sorting motifs (YXX⌽) and a single acidic cluster dileucine motif (DXXLL), both of which have been shown to target herpesvirus proteins to the Golgi apparatus (2,20,28,30).…”

Section: -Kda Protein Alone With Similar Results (Data Not Shown)mentioning

confidence: 85%

Characterization of a Novel Golgi Apparatus-Localized Latency Determinant Encoded by Human Cytomegalovirus

Petrucelli¹,

Rak²,

Grainger³

et al. 2009

J Virol

104

254

View full text Add to dashboard Cite

Human cytomegalovirus (HCMV) exists indefinitely in infected individuals by a yet poorly characterized latent infection in hematopoietic cells. We previously demonstrated a requirement for the putative UL138 open reading frame (ORF) in promoting a latent infection in CD34؉ hematopoietic progenitor cells (HPCs) infected in vitro. In our present study, we have identified two coterminal transcripts of 2.7 and 3.6 kb and a 21-kilodalton (kDa) protein (pUL138) that are derived from the UL138 locus with early-late gene kinetics during productive infection. The UL138 transcripts and protein are detected in both fibroblasts and HPCs. A recombinant virus, FIX-UL138 STOP , that synthesizes the UL138 transcripts but not the protein exhibited a partial loss-of-latency phenotype in HPCs, similar to the phenotype observed for the UL138-null recombinant virus. This finding suggests that the UL138 protein is required for latency, but it does not exclude the possibility that the UL138 transcripts or other ORFs also contribute to latency. The mechanisms by which pUL138 contributes to latency remain unknown. While the 86-and 72-kDa immediate-early proteins were not detected in HPCs infected with HCMV in vitro, pUL138 did not function directly to suppress expression from the major immediate-early promoter in reporter assays. Interestingly, pUL138 localizes to the Golgi apparatus in infected cells but is not incorporated into virus particles. The localization of pUL138 to the Golgi apparatus suggests that pUL138 contributes to HCMV latency by a novel mechanism. pUL138 is the first HCMV protein demonstrated to promote an infection with the hallmarks of latency in CD34 ؉ HPCs.

show abstract

“…The human body relies mainly on cellular immunity to protect against CMV (17). CMV is known to evade the immune system through a variety of mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Bruton’s agammaglobulinemia in an adult male due to a novel mutation: a case report

Liu

et al. 2016

J. Thorac. Dis.

View full text Add to dashboard Cite

X-linked agammaglobulinemia (XLA) is caused by mutation in the gene coding for Bruton's tyrosine kinase (BTK), which impairs peripheral B cell maturation and hypogammaglobulinemia. In this report, we present a case of XLA in a 22-year-old adult male. Genetic testing revealed a novel mutation located at the conserved region (c.383T>C). The patient had a history of recurrent respiratory tract infection which eventually progressed to chronic type II respiratory failure. Several pathogenic bacteria were isolated on culture of respiratory secretions obtained on bronchoscopy. The patient improved on treatment with antibiotics.

show abstract

Human Cytomegalovirus Regulates Surface Expression of the Viral Protein UL18 by Means of Two Motifs Present in the Cytoplasmic Tail

Cited by 8 publications

References 50 publications

NKG2D Ligand MICA Is Retained in thecis-Golgi Apparatus by Human Cytomegalovirus Protein UL142

NKG2D Ligand MICA Is Retained in thecis-Golgi Apparatus by Human Cytomegalovirus Protein UL142

Characterization of a Novel Golgi Apparatus-Localized Latency Determinant Encoded by Human Cytomegalovirus

Bruton’s agammaglobulinemia in an adult male due to a novel mutation: a case report

Contact Info

Product

Resources

About