Post-translational modification by ubiquitin molecules is a key regulatory process for stem cell fate determination. Ubiquitination and deubiquitination are the major cellular processes used to balance the protein turnover of several transcription factors that regulate stem cell differentiation. Deubiquitinating enzymes (DUBs), which facilitate the processing of ubiquitin, significantly influence stem cell fate choices. Specifically, DUBs play a critical regulatory role during development by directing the production of new specialized cells. This review focuses on the regulatory role of DUBs in various cellular processes, including stem cell pluripotency and differentiation, adult stem cell signaling, cellular reprogramming, spermatogenesis, and oogenesis. Specifically, the identification of interactions of DUBs with core transcription factors has provided new insight into the role of DUBs in regulating stem cell fate determination. Thus, DUBs have emerged as key pharmacologic targets in the search to develop highly specific agents to treat various illnesses. STEM CELLS 2017;35:9-16
SIGNIFICANCE STATEMENTThe review is written from a unique perspective in overseeing the regulatory role of deubiquitinating enzymes in stem cells. A great attention has been given to the physiological role of ubiquitination system in regulating pluripotency of embryonic stem cells. However, the reversal of ubiquitination by deubiquitinating enzymes plays an equally important role in the regulation of levels of expression of the stemness-related proteins by preventing its ubiquitination. This is timely topic, given that this is the first review article attempting to discuss the accumulated evidence suggesting the critical role of deubiquitinating enzymes in regulating stem cell fate determination process such as maintenance of pluripotency, differentiation, cellular reprogramming, spermatogenesis, and oogenesis. Beyond this, the review provide us the clue for the remaining challenges in developing DUBs as targets for stem cell therapeutics.