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.
Highlights
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a member of the c2- herpesvirus genus
dendritic cells (DCs)-SIGN and DC-SIGNR can act as co-receptors for KSHV It has been documented that DC-SIGN can act a co-receptor for KSHV, not sufficient for entry by itself, but capable of enhancing viral infectivity [26,27,28]
24 hours post-transfection, cells were infected with a low multiplicity of infection (MOI) (0.01) of recombinant KSHV derived from the Bac16 construct, lacking both K3 and K5 genes and expressing green fluorescent protein (GFP) from a constitutive promoter, or cells were left uninfected as controls
Summary
Kaposi’s sarcoma-associated herpesvirus (KSHV) is a member of the c2- herpesvirus genus. K3 and K5 each contain a RINGCH type zinc finger domain at their N-termini, and are the prototypical members of the MARCH (membrane-associated RING-CH containing) family of proteins [8,9]. These viral proteins, like all of the MARCH family members, have been found to act as E3 ubiquitin ligases, with the RING-CH domain being important for this function [10,11,12,13] They have been shown to mediate the down regulation of several immunomodulatory proteins, including B7.2 (CD86), intercellular adhesion molecule 1 (ICAM-1; CD54), tetherin (BST-2), IFN-cR and several major histocompatibility complex (MHC) class I haplotypes, as well as additional cellular proteins less tightly linked with immune function, such as CD31 [8,10,14,15,16,17,18,19,20]. Some cellular proteins are targeted by the MARCH proteins for endocytosis, some are blocked for exocytosis, and some targets are regulated by multiple mechanisms [11,21]
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