Kidney cell injury may be associated with protein misfolding and induction of endoplasmic reticulum (ER) stress. Examples include complement-induced glomerular epithelial cell (GEC)/podocyte injury in membranous nephropathy, and ischemia-reperfusion injury. Renal cell injury can also result from mutations in integral proteins, which lead to their misfolding and accumulation. Certain nephrin missense mutants misfold, accumulate in the ER, and induce ER stress. We examined if enhancement of ubiquitin-proteasome system (UPS) function may facilitate proteostasis and confer protection against injury. Ubiquitin-specific protease 14 (Usp14) is reported to retard proteasomal protein degradation. Thus, inhibition of Usp14 may enhance degradation of misfolded proteins, and attenuate cell injury. In GEC, the reporter proteins, GFPu (a "misfolded" protein) and CD3delta (an ER-associated degradation substrate) undergo time-dependent proteasomal degradation. Complement did not affect degradation of CD3delta-YFP, but accelerated degradation of GFPu, and the Usp14-directed inhibitor, IU1, further accelerated this degradation. Conversely, overexpression of Usp14 reduced degradation of GFPu and CD3delta-YFP. In 293T cells, IU1 did not enhance degradation of disease-associated nephrin missense mutants, I171N and S724C, whereas overexpression of Usp14 reduced degradation. IU1 was cytoprotective after injury induced by the ER stressor, tunicamycin, and in vitro ischemia-reperfusion, but did not affect complement-induced cytotoxicity. In conclusion, Usp14 controls proteasomal degradation of some misfolded proteins. In addition, a Usp14-directed inhibitor reduces cytotoxicity in the context of global protein misfolding during certain types of renal cell injury.