The human cytomegalovirus protein UL147A downregulates the most prevalent MICA allele: MICA*008, to evade NK cell-mediated killing

Abstract

Natural killer (NK) cells are innate immune lymphocytes capable of killing target cells without prior sensitization. One pivotal activating NK receptor is NKG2D, which binds a family of eight ligands, including the major histocompatibility complex (MHC) class I-related chain A (MICA). Human cytomegalovirus (HCMV) is a ubiquitous betaherpesvirus causing morbidity and mortality in immunosuppressed patients and congenitally infected infants. HCMV encodes multiple antagonists of NK cell activation, including many mechanisms targeting MICA. However, only one of these mechanisms, the HCMV protein US9, counters the most prevalent MICA allele, MICA*008. Here, we discover that a hitherto uncharacterized HCMV protein, UL147A, specifically downregulates MICA*008. UL147A primarily induces MICA*008 maturation arrest, and additionally targets it to proteasomal degradation, acting additively with US9 during HCMV infection. Thus, UL147A hinders NKG2D-mediated elimination of HCMV-infected cells by NK cells. Mechanistic analyses disclose that the non-canonical GPI anchoring pathway of immature MICA*008 constitutes the determinant of UL147A specificity for this MICA allele. These findings advance our understanding of the complex and rapidly evolving HCMV immune evasion mechanisms, which may facilitate the development of antiviral drugs and vaccines.

Suppression of MR1 by human cytomegalovirus inhibits MAIT cell activation

“…US3 (66)) (reviewed in (71)). Indeed, although US9 is capable of reducing MICA*008 surface expression in isolation, a HCMV deletion mutant lacking US9 is still capable of reducing MICA*008 surface levels (48) consistent with the recent definition of pUL147A as an additional HCMV encoded immunevasin targeting MICA*008 (47).…”

“…This is unsurprising given that HCMV encodes a number of functional proteins to target the same pathway e.g. MICA (44,45,47,48), MHC I (71), FcgR activation (83). We predict that HCMV encodes additional gene product(s) to target MR1 that will be a focus of future studies.…”

“…Conversely HLA-G, a non-classical MHC I-like molecule that functions as an NK activation inhibitor, is targeted for proteasomal degradation by HCMV gpUS10 in infected HeLa cells (42) and trophoblasts (43). MHC I chain-related proteins A and B (MICA and MICB) which are highly polymorphic stress-induced NKG2D ligands that are similar to the MHC I heavy chain but do not associate with b2M, are both targeted for downregulation by HCMV (44)(45)(46)(47)(48). Our previous demonstration of MR1 downregulation by herpesviruses, with a focus on HSV-1 and VZV (49,50), also indicated that both HCMV and murine cytomegalovirus were capable of inhibiting MR1 surface expression, however the functional outcome and the role of specific gene functions in such regulation was not studied.…”

microRNA, a Subtle Indicator of Human Cytomegalovirus against Host Immune Cells

“…NK cells are an important component of the innate immune system to fight against HCMV infection. Studies have found multiple genetic loci (e.g., UL16 and UL142; UL = unique long) in the HCMV genome, and their transcripts inhibit NK cell recognition [30]. Natural killer Group 2 member D (NKG2D) belongs to the C-type lectin-like activating re-ceptor family that is expressed ubiquitously on all NK cells to mediate immune surveillance on virus-infected cells after binding with NKG2D ligands (NKG2DLs).…”

Evasion of the Host Immune Response by Betaherpesviruses

“…The mutant’s surface expression was significantly decreased compared to wild type MICB. In addition, MRC-5 human lung fibroblasts were targeted for killing by NK cells when expressing a mutation in the UL147a gene [ 102 ].…”