Chaperones are
proteins that assist the noncovalent folding and assembly of macromolecular
polypeptide chains, ultimately preventing the formation of nonfunctional or potentially toxic
protein aggregates. Plasma cell-induced-endoplasmic reticulum (ER)-resident
protein 1 (pERP1) is a cellular chaperone that is preferentially expressed in marginal-zone B cells and is highly upregulated during plasma cell differentiation. While initially identified as a dedicated factor for the assembly of secreted
IgM, pERP1 has since been implicated in suppressing
calcium mobilization, and its expression is misregulated in multiple
tumors. A number of herpesvirus immediate early gene products play important roles in the regulation of viral gene expression and/or evasion of host immune responses. Here, we report that the Kaposi's sarcoma-associated herpesvirus (KSHV) immediate early viral gene K4.2 encodes an endoplasmic reticulum-localized
protein that interacts with and inhibits pERP1. Consequently, K4.2 expression interfered with
immunoglobulin secretion by delaying the kinetics of
immunoglobulin assembly and also led to increased responsiveness of B-cell receptor signal transduction by enhancing
phosphotyrosine signals and intracellular
calcium fluxes. Furthermore, K4.2 expression also appeared to contribute to maximal lytic replication by enhancing viral
glycoprotein expression levels and ultimately promoting infectious-virus production. Finally, immunohistochemistry analysis showed that pERP1 expression was readily detected in KSHV-positive cells from
multicentric Castleman's disease (MCD) and
Kaposi's sarcoma (KS) lesions, suggesting that pERP1 may have potential roles in the KSHV life cycle and
malignancy. In conclusion, our data suggest that K4.2 participates in lytic replication by enhancing
calcium flux and viral
glycoprotein expression, but also by interfering with
immunoglobulin assembly to potentially dampen the adaptive immune response.