A cytomegalovirus immunevasin triggers integrated stress response-dependent reorganization of the endoplasmic reticulum.

Human cytomegalovirus (HCMV) encodes an ER-resident glycoprotein, UL148, which activates the unfolded protein response (UPR) but is fully dispensable for viral replication in cultured cells. Hence, its previously ascribed roles in immune evasion and modulation of viral cell tropism are hypothesized to cause ER stress. Here, we show that UL148 is necessary and sufficient to drive the formation of large ER- derived structures that occupy up to 7% of the infected cell cytosol. The structures are found to be sites where UL148 coalesces together with cellular proteins involved in ER quality control, such as Hrd1 and EDEM1. Ultrastructural analyses of the structures reveal tortuous, densely packed segments of collapsed ER which connect to distended cisternae. Notably, UL148 accumulates in a detergent-insoluble form during infection while a homologous rhesus cytomegalovirus immunevasin that fails to cause ER reorganization remains soluble. During induced ectopic expression of a UL148-GFP fusion protein, punctate signals traffic to accumulate at prominent structures that exhibit poor recovery of fluorescence after photobleaching. Small molecule blockade of the integrated stress response (ISR) prevents the formation of puncta, leading to a uniform reticular fluorescent signal. Accordingly, ISR inhibition during HCMV infection abolishes the coalescence of UL148 and Hrd1 into discrete structures. Given that UL148 stabilizes immature forms of a receptor binding subunit for a viral envelope glycoprotein complex of pivotal importance for HCMV infectivity, which is otherwise particularly susceptible to ER associated degradation, our results imply that stress-dependent ER remodeling contributes to viral cell tropism.