(A) A ubiquitin tag is added to proteins that need to be degraded, including unfolded, misfolded, nonnative, or oxidized proteins. Two main pathways recruit ubiquitinated proteins to the proteasome: the first relies on intraproteasomal polyubiquitin receptors Rpn10/Rpn13 in the 19S RP, which directly binds polyubiquitin; the second depends upon extraproteasomal ubiquitin receptors, such as Ubqln1 (yellow). Ubqln1 functions as a “shuttle-factor” by binding to ubiquitinated proteins via its UBA domain and subsequently interacts with Rpn10 in the proteasome via its UBL domain. (B) During I/R injury, unfolded, misfolded, and oxidized proteins are increased, putting greater demand on the UPS. Hu et al. reveal that Ubqln1 expression increases with I/R and that loss of Ubqln1 exacerbates, while ubiquitous overexpression of an Ubqln1 transgene ameliorates, myocardial I/R injury. In cultured cardiomyocytes, Ubqln1 overexpression facilitated proteasome-mediated degradation of oxidized proteins.