Divergent dependence on host gene sigma-1 receptor shapes hepatitis C and orthoflavivirus infection

The Flaviviridae family encompasses major human pathogens, such as hepatitis C virus (HCV) and dengue virus (DENV). Despite shared genome organization and replication strategies, these viruses differ in host interactions, tissue tropism and replication dynamics, leading to distinct disease outcomes. Sigma-1 receptor (SIGMAR1) encodes an endoplasmic reticulum-associated protein that regulates lipid transport, autophagy and proteostasis. We previously showed that SIGMAR1 silencing reduces early HCV infection efficiency without affecting unrelated viruses. Here, we demonstrate that SIGMAR1 is rate-limiting for the formation of normal double-membrane vesicles (DMVs), the putative HCV replication compartments. In contrast, DENV and West Nile virus (WNV) RNA replication remained efficient following SIGMAR1 depletion, indicating a selective requirement for SIGMAR1 in HCV DMV formation. Notably, SIGMAR1 knockdown markedly impaired secretion of infectious DENV and WNV particles without reducing intracellular progeny, suggesting a role for SIGMAR1 in orthoflavivirus virion release. SIGMAR1 silencing also disrupted Golgi architecture and altered cellular detergent-resistant membrane composition, consistent with defects in vesicular trafficking. These findings identify SIGMAR1 as a host factor with distinct functions in the replication cycles of hepaciviruses and orthoflaviviruses and highlight its broader role in maintaining membrane organization required for efficient infection by Flaviviridae .