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

S Kim et al., Nat Immno.. 12: 984-91, (2011)

Speaker: Chia-Ming Chang (張家銘)                    Time: 13:10~14:00, Mar. 14, 2012

Commentator: Dr. Yao Chang (張堯老師)           Place: Room 601

Abstract:

MicroRNA(miRNA), a small non-coding RNA, plays an important role in gene regulation. MiRNAs participate in viral infection and innate immunity responses. Human cytomegalovirus (HCMV), remains latent in host after infection just like others herpesviruses. It is well known that unique short region(US) of HCMV may encode protein that inhibits major histocompatibility complex I (MHC class-I)¹ to escape immune response by different pathways. In this study, the authors revealed a new mechanism that HCMV inhibits CD8⁺ T cell activity by encoding miRNA miR-US4-1 to target its target gene ERAP1. ERAP-1, also called A-LAP, ARTS-1 or PILS-AP, plays an important role in antigen presenting of MHC-I to CD8⁺ T cells. ERAP1 functions as a “peptide ruler” to trim precursor peptides produced by ubiquitin or proteasome to the mature peptides². Initially, the authors clarified that ERAP1 RNA and protein was down-regulated in miR-US4-1 over-expressed cell by directly binding of RISC-Ago-miRNA complex with the mRNA of ERAP-1b target gene. Subsequently, the authors measured ERAP-1 expression level in HCMV infected cells. The results showed that HCMV AD169 infection indeed down-regulated ERAP-1 expression. This down-regulation of ERAP1 expression was rescued when the cells were infected by US4 deletion recombinant virus. Finally, the authors revealed that miR-US4-1 inhibits CD8⁺ T cell activity and peptide processing activity by cytotoxic T-lymphocyte assay and OVA8 experimental system. In summary, this study reveals a new mechanism which HCMV used to escape immune response by encoding microRNA miR-US4-1, and provide a new antiviral target.

Reference:

1.         Stern-Ginossar, N. et al. Host immune system gene targeting by a viral miRNA. Science 317, 376-381 (2007).

2.         Nguyen, T.T. et al. Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1. Nature structural & molecular biology 18, 604-613 (2011).