Immune evasion by a novel family of viral PHD/LAP-finger proteins of gamma-2 herpesviruses and poxviruses.
Many viruses have developed mechanisms to escape the cellular immune response by inhibiting antigen presentation from major histocompatibility complex (MHC) molecules. Most of these immune escape mechanisms are highly host adapted and specific to a given virus species or family. Recent observations however, suggest that a conserved family of viral proteins is used by both gamma-2 herpesviruses and by poxviruses to downregulate MHC class I. In addition, other cell surface molecules involved in immune recognition by T cells and NK cells are also downregulated. Two open reading frames (ORFs), K3 and K5, of Kaposi's sarcoma associated virus (KSHV) and one ORFs, K3, of murine gamma herpesvirus 68 (MHV 68) inhibit surface expression of MHC I molecules. In cells transfected with KSHV-K3 and KSHV-K5, MHC I is rapidly endocytosed and degraded in lysosomes whereas in MHV 68-K3 transfected cells, MHC I is targeted for proteasomal degradation. The K3 and K5 genes display a characteristic conserved domain structure of an amino-terminal plant homeo domain/leukemia associated protein-zinc finger domain followed by two carboxyterminal transmembrane domains. Related proteins are not only found in other gamma-2 herpesviruses, but also in several poxviruses. Moreover, recent data suggest that the K3-related protein of myxoma virus also downregulates MHC I. The presence of similar genes in eukaryotic genomes further indicates that the viral ORFs were originally derived from host genes of as yet unknown function. The molecular mechanism of MHC I downregulation by this novel gene family is only poorly understood at present. However, several lines of evidence suggest that they might function as ubiquitin ligases that regulate the intracellular transport of transmembrane proteins through ubiquitination.
Früh
Klaus
K
Oregon Health and Science University, Vaccine and Gene Therapy Institute, 505 NW 185th Avenue, Beaverton, OR 97006, USA. fruehk@ohsu.edu
Bartee
Eric
E
Gouveia
Kristine
K
Mansouri
Mandana
M
D000595:Amino Acid Sequence; D000818:Animals; D015536:Down-Regulation; D018142:Gammaherpesvirinae / Q000472:pathogenicity*; D006566:Herpesviridae Infections / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D011212:Poxviridae / Q000472:pathogenicity*; D011213:Poxviridae Infections / Q000276:immunology*; D011817:Rabbits; D025801:Ubiquitin / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism*; D016335:Zinc Fingers
D015395:Histocompatibility Antigens Class I; D025801:Ubiquitin; D014764:Viral Proteins