Human Cytomegalovirus US3 Gene Expression Is Regulated by a Complex Network of Positive and Negative Regulators

Abstract

One immediate early gene of human cytomegalovirus, the US3 gene, causes retention of major histocompatibility locus class I heavy chain proteins in the endoplasmic reticulum and is postulated to have a role in viral pathogenicity. Expression of the US3 gene is regulated by a number of cis-acting elements. In addition, numerous viral proteins are involved in regulating US3 gene expression. US3 transcription was activated modestly by a virion protein, ppUL82. The immediate early proteins encoded by UL122–123 (IE1 and IE2) further activate US3 expression, with the activation enhanced by expression of pTRS1. Other proteins, the immediate early protein encoded by UL37ex1/UL38 and the early protein, pUL84, inhibited IE1 and IE2 activation of US3 expression. US3 transcription is regulated both positively and negatively by a complex network of viral proteins, the interaction of which contributes to precise regulation of US3 gene expression. The ability of pUL37ex1/UL38 to repress expression of the immediate early US3 gene while activating early gene expression suggests that pUL37ex1/UL38 may function to switch viral gene expression from immediate early to early genes.