Human cytomegalovirus microRNA miR-US4-1 inhibits CD8+ T cell responses by targeting the aminopeptidase ERAP1

Abstract

The major histocompatibility complex (MHC) class I molecules present peptides on the cell surface by CD8 + T cells, which is critical for killing of virally infected or transformed cells. Precursors of MHC class I-presented peptides are trimmed to mature epitopes by endoplasmic reticulum aminopeptidase 1 (ERAP1). The US2-US11 genomic region of human cytomegalovirus (HCMV) is dispensable for viral replication and harbors 3 microRNAs (miRNAs). We show here the HCMV miR-US4-1 specifically down-regulates ERAP1 expression during viral infection. Accordingly, the trimming of HCMV-derived peptides is inhibited, leading to reduced susceptibility of infected cells to HCMV-specific cytotoxic T lymphocytes (CTLs). Our findings reveal a novel viral miRNA-based CTL evasion mechanism that targets a key step in the MHC class I antigen-processing pathway.MHC class I molecule binds peptides and presents them on the cell surface for recognition by CD8 + T cells. Cytosolic peptides generated by the proteasomes and prematurely translated peptides are transported to the endoplasmic reticulum (ER) through the transporter associated with antigen processing (TAP) complex 1, 2 . Some of these peptides are further processed by ER-resident aminopeptidases, such as ERAP1, and peptide trimming by ERAP1 (also known as A-LAP, ARTS-1, and PILS-AP) in the ER is a crucial step for determining the quality and quantity of optimal antigenic peptide production and the stability of the MHC class I-β 2 m-peptide heterotrimer [3][4][5][6] . ERAP1 trims relatively long * To whom correspondence should be addressed: Department of Biological Sciences, Seoul National University, Seoul 151-747, Korea, (Phone) +822-880-9233 (Fax) +822-872-1993 S.R.R cloned the HCMV-specific CTLs. S.K and K.A designed the overall study and wrote the paper. NIH Public AccessAuthor Manuscript Nat Immunol. Author manuscript; available in PMC 2012 December 20. peptides efficiently in a sequence-specific manner, resulting in the accumulation of 8-9 amino acid-long optimal peptides 5,7,8 . ERAP1 therefore acts as a 'molecular ruler' for antigenic peptide production 9 . In addition, genome-wide association studies have associated nonsynonymous single nucleotide polymorphisms in ERAP1 with ankylosing spondylitis 4 . Additionally, ERAP1 has non-peptide processing functions via its role in shedding of cytokine receptors 4 .MiRNAs are small RNAs 19 to 23 nucleotides long that regulate gene expression by complete or partial base-pairing with the 3′-untranslated region (UTR) of their target mRNA which leads to mRNA cleavage, destabilization, or translational repression 10 . Since the first report in 2004 that viruses express miRNAs 11 , numerous viral miRNAs have been discovered and are mainly related to viral proliferation and survival-related immune evasion, although this is based on a limited number of studies 12 . The β-herpesvirus HCMV expresses at least 14 miRNAs during productive infection 13,14 . One HCMV-encoded miRNA, miR-UL112-1 targets 3 HCMV genes involved in viral r...

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

“…CMV is known to evade the immune system through a variety of mechanisms. There was still a risk of acute exacerbation of chronic bronchial CMV infection although the cellular immune function was normal or even increased (18)(19)(20)(21).…”

MicroRNAs in the regulation of TLR and RIG-I pathways

“…[114][115][116] HCMV miR-US4-1 specifically downregulates ERAP1, which participates in trimming MHC class I-presented peptide precursors to mature epitopes. 117 Accordingly, the trimming of HCMV-derived peptides is inhibited, leading to decreased susceptibility of infected cells to HCMV-specific cytotoxic T lymphocytes, thus helping identify a previously unknown viral miRNA-based cytotoxic T lymphocyte-evasion mechanism. MiRNAs encoded by simian virus 40, accumulate at late times and perfectly target viral T antigen mRNAs without reducing the infectious viral yield.…”

microRNAs function in CD8+T cell biology

“…Through the direct targeting of SOCS1, miR-155 augments production of IL-12p70 by DCs [88], which results in increased effector CD8 + T cell-mediated IFN-g expression and promotes antiviral and antitumor responses [89,90]. Furthermore, CD8 + T cell-effector functions can be inhibited indirectly by miR-US4-1 during infection with HCMV [91]. This activity is attributed to the ability of miR-US4-1 to repress aminopeptidase ERAP1b, a factor that is required for the production of antigenic peptides, and thereby interfere with the presentation of antigenic peptides to CD8 + T cells [91,92].…”