title: Kaposi's sarcoma-associated herpesvirus K3 and K5 proteins down regulate both DC-SIGN and DC-SIGNR.
abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of multicentric Castleman's disease, primary effusion lymphoma and Kaposi's sarcoma. In this study, we show that like the C-type lectin DC-SIGN, the closely related DC-SIGNR can also enhance KSHV infection. Following infection, they are both targeted for down modulation and our data indicate that the KSHV MARCH-family ubiquitin ligase K5 is mediating this regulation and subsequent targeting for degradation of DC-SIGN and DC-SIGNR in the context of the virus. The closely related viral K3 protein, is also able to target these lectins in exogenous expressions studies, but only weakly during viral infection. In addition to requiring a functional RING-CH domain, several protein trafficking motifs in the C-terminal region of both K3 and K5 are important in regulation of DC-SIGN and DC-SIGNR. Further exploration of this modulation revealed that DC-SIGN is endocytosed from the cell surface in THP-1 monocytes, but degraded from an internal location with minimal endocytosis in HEK-293 cells. Pull-down data indicate that both K3 and K5 preferentially associate with immature forms of the lectins, mediating their ubiquitylation and degradation. Together, these data emphasize the molecular complexities of K3 and K5, while expanding the repertoire of targets of these two viral proteins.
authors: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors: Sabine M
authors: SM
authors: Lang
authors: Meisha O F
authors: MO
authors: Bynoe
authors: Roshan
authors: R
authors: Karki
authors: Michael A
authors: MA
authors: Tartell
authors: Robert E
authors: RE
authors: Means
mesh_terms: D020816:Amino Acid Motifs; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D015536:Down-Regulation; D004705:Endocytosis; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D047468:Immunoprecipitation; D037181:Lectins, C-Type / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000378:metabolism; D054875:Ubiquitination; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D046988:Proteasome Endopeptidase Complex; D011956:Receptors, Cell Surface; D014443:Tyrosine; D014764:Viral Proteins; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C433029:CLEC4M protein, human; C456022:K3 protein, Kaposi's sarcoma-associated herpesvirus