Ubiquitin carboxyl-terminal hydrolase 5

Ubiquitin carboxyl-terminal hydrolase 5 (USP5) is a deubiquitinating enzyme that cleaves isopeptide bonds on ubiquitin and substrate proteins to regulate cellular processes including NF-κB signaling, Wnt/β-catenin pathways, and autophagy (UniProt: P45974). The protein stabilizes key regulatory proteins such as FOXM1, TXNIP, and IRF3, and participates in stress granule assembly, inflammatory responses, and type I interferon production through selective removal of different polyubiquitin chain types.

USP5 is expressed broadly and functions as a negative regulator of multiple homeostatic pathways including autophagy and interferon signaling (UniProt: P45974). Its role in ubiquitin-dependent protein degradation affects diverse cellular processes from T-cell biology to DNA mismatch repair.

In Alzheimer's disease, USP5 shows decreased expression in post-mortem AD brain tissue compared to age-matched controls (Chaparral AD proteomics), with a mean log2 fold-change of −0.458. This downregulation may have implications for autophagy capacity and inflammatory control in the AD brain, given USP5's roles as a negative regulator of both autophagy and type I interferon production.