UC Berkeley

Kaposi sarcoma-associated herpesvirus (KSHV) encodes for MIR2, a RING-finger E3 ubiquitin ligase that mediates ubiquitination and degradation of cellular proteins important for the establishment of an efficient antiviral immune response. How MIR2 targets its cellular substrates is poorly understood. I found that palmitoylation, a post-translational modification, is important for MIR2 function and is required for interaction with a subset of its substrates. Palmitoylation may act to regulate MIR2 function and localization during viral infection by allowing MIR2 to gain greater access to immunostimulatory molecules localized to lipid rafts; specialized subcellular compartments known to be important for immune cell activation.

The molecular mechanisms involved in MIR-mediated ubiquitination of cellular substrates have not been well characterized. Ubiquitination is a highly conserved process known to be involved in a wide range of cellular pathways. This modification involves the covalent attachment of an ubiquitin molecule directly to the amino group of a substrate lysine. Our lab recently showed that the MIR proteins can ubiquitinate substrate molecules on non-lysine residues, a process now referred to as unconventional ubiquitination. I investigated whether this was a unique property of the MIR proteins or if this is a property shared among many E3 ubiquitin ligases. Interestingly, I identified a cellular E3 ubiquitin ligase (Hrd1) that can also perform unconventional ubiquitination in a globally used pathway (ER-Associated Degradation pathway). Altogether, these results strongly suggest that unconventional ubiquitination is more prevalent than once thought, and may be necessary to ensure the degradation of a highly diverse array of substrates, especially when lysine residues are inaccessible.