Ubiquitin carboxyl-terminal hydrolase 14

USP14 (ubiquitin carboxyl-terminal hydrolase 14) is a proteasome-associated deubiquitinase that releases ubiquitin from polyubiquitinated proteins targeted for proteasomal degradation, thereby enabling ubiquitin recycling (UniProt: P54578). The protein exists both as a reversibly bound proteasome subunit and as a cytoplasmic pool, and also modulates endoplasmic reticulum-associated protein degradation through interaction with ERN1.

USP14 participates in multiple cellular processes including synaptic function at neuromuscular junctions, CXCR4 trafficking, viral defense via CGAS stabilization, and selective autophagy regulation through inhibition of OPTN-mediated KDM4D degradation (UniProt: P54578). These functions implicate the protein in proteostasis and neuronal homeostasis.

In Alzheimer's disease, USP14 shows ambiguous regulation across subcellular fractions in human post-mortem AD brain tissue compared to age-matched controls (Chaparral AD proteomics), with a mean log2 fold-change of −0.10, indicating minimal average change. The direction classification reflects variable protein abundance across the four fractions examined (P2, P3, S2, S3), precluding a clear up- or down-regulation assignment in this TMT-labeled proteomics dataset.