Human cytomegalovirus US3 gene expression is regulated by a complex network of positive and negative regulators

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.