Human cytomegalovirus protein UL13 targets to mitochondria to induce cuproptosis.

Human cytomegalovirus (HCMV) is a pathogenic β-herpesvirus that causes severe diseases in immunocompromised individuals. HCMV has evolved diverse strategies to manipulate host cellular processes to facilitate its replication and evade immune surveillance. Here, we identified the HCMV-encoded protein UL13 as a potent inducer of cuproptosis, a recently discovered form of copper-dependent cell death. Overexpression of UL13 induces the canonical hallmarks of cuproptosis, including oligomerization of dihydrolipoamide S-acetyltransferase (DLAT), depletion of iron-sulfur (Fe-S) cluster proteins, and accumulation of mitochondrial copper. Knockdown of UL13 inhibits HCMV-induced DLAT oligomerization and cuproptosis. UL13 is localized to the mitochondria, where it associates with the inner mitochondrial membrane copper transporter SLC25A3, leading to an excessive accumulation of mitochondrial copper. Knockout of SLC25A3 abrogates UL13-induced DLAT oligomerization and rescues cells from cuproptotic death. Our findings reveal a mechanism by which HCMV hijacks host copper homeostasis to trigger cell death, providing new insights into viral pathogenesis and the complex virus-host interplay.