Internal cleavage of the human cytomegalovirus UL37 immediate-early glycoprotein and divergent trafficking of its proteolytic fragments

Abstract

The human cytomegalovirus UL37 gene encodes at least three isoforms, which share N-terminal UL37 exon 1 (UL37x1) sequences. UL37 proteins traffic dually into the endoplasmic reticulum (ER) and to mitochondria. Trafficking of the UL37 glycoprotein (gpUL37) in relation to its post-translational processing was investigated. gpUL37 is internally cleaved in the ER and its products traffic differentially. Its C-terminal fragment (UL37COOH) is ER-localized and N-glycosylated. Unlike conventional ER signal sequences, its N-terminal () fragment is stable and traffics to mitochondria. Inhibition of N-glycosylation did not block pUL37 cleavage and dramatically decreased the levels of but not of UL37COOH. pUL37M, which differs from gpUL37 by the lack of residues 178–262 and hence the UL37x3 consensus signal peptidase cleavage site, traffics into the ER and mitochondria, but is neither cleaved nor N-glycosylated. This finding of a relationship between ER processing and mitochondrial importation of UL37 proteins is unique for herpesvirus proteins.