The Pleiotropic Ubiquitin-Specific Peptidase 16 and Its Many Substrates

Abstract

Ubiquitin-specific peptidase 16 (USP16) is a deubiquitinase that plays a role in the regulation of gene expression, cell cycle progression, and various other functions. It was originally identified as the major deubiquitinase for histone H2A and has since been found to deubiquitinate a range of other substrates, including proteins from both the cytoplasm and nucleus. USP16 is phosphorylated when cells enter mitosis and dephosphorylated during the metaphase/anaphase transition. While much of USP16 is localized in the cytoplasm, separating the enzyme from its substrates is considered an important regulatory mechanism. Some of the functions that USP16 has been linked to include DNA damage repair, immune disease, tumorigenesis, protein synthesis, coronary artery health, and male infertility. The strong connection to immune response and the fact that multiple oncogene products are substrates of USP16 suggests that USP16 may be a potential therapeutic target for the treatment of certain human diseases.

Increasing the Throughput and Reproducibility of Activity-Based Proteome Profiling Studies with Hyperplexing and Intelligent Data Acquisition

“…USP22 Cys 494 (87.5% occupancy by KB03) is localized in the USP domain, 25 and USP16/Ubp-M Cys 191 (78% occupancy by G92) is adjacent to the USP domain. 26 Both of these sites were also liganded in the whole-cell lysate analysis, further supporting the finding of the nuclear fractionation experiment ( Fig. 4C ).…”

Increasing the Throughput and Reproducibility of Activity-Based Proteome Profiling Studies with Hyperplexing and Intelligent Data Acquisition

“…DUB enzymes ubiquitin carboxyl-terminal hydrolase 16 and 22 (USP16 and USP22) function in the transcription regulation in the nucleus through deubiquitination of histone substrates (reviewed in ref ). USP22 Cys 494 (87.5% occupancy by KB03) is localized in the USP domain, and USP16/Ubp-M Cys 191 (78% occupancy by G92) is adjacent to the USP domain . Both of these sites were also liganded in the whole-cell lysate analysis, further supporting the finding of the nuclear fractionation experiment (Figure A).…”

“…USP22 Cys 494 (87.5% occupancy by KB03) is localized in the USP domain, 29 and USP16/Ubp-M Cys 191 (78% occupancy by G92) is adjacent to the USP domain. 30 Both of these sites were also liganded in the whole-cell lysate analysis, further supporting the finding of the nuclear fractionation experiment (Figure 5A). We also observed ligandable sites on three E3 ubiquitin ligases, UBR2, UBR4, and UBR5 that function in the N-end rule proteolytic pathway.…”

USP16 is an ISG15 cross-reactive deubiquitinase that targets pro-ISG15 and ISGylated proteins involved in metabolism

“…USP16 was initially identified as a DUB that removes Ub from lysine119 of H2A ( 33 , 65 ). Many other ubiquitinated substrates for USP16 have been identified so far ( 66 ). The USP16-dependent ISG15 interactome identified in our experiments contained mostly cytoplasmic proteins, suggesting that USP16 exerts its function there.…”