Novel proteases with deubiquitylation activity: examination of function in T lymphocytes

Work over the last 25 years has established the importance of regulating protein ubiquitylation in a wide range of cellular functions including cell cycle control, transcriptional regulation, and cell signaling. These processes are disturbed in many human diseases such as cancer, neurodegeneration and immunological disorders. So far, most analyses have focused on mechanisms controlling ubiquitin ligation. However, the recognition of extensive classes of deubiquitylating enzymes (DUBs) strongly suggests a regulatory (as opposed to purely recycling) role for DUBs. Thus it is anticipated that the planned analysis of one class of these enzymes would shed light on important and medically relevant aspects of cellular physiology. A novel class of these enzymes containing an ovarian tumor domain (OTU), which encodes for a putative ubiquitin-specific cysteine protease, has been recently identified. This domain is conserved throughout evolution. Obubain 1 (OTUB1), a member of this protein family, does not contribute to the deubiquitylation of the bulk of cytosolic proteins. Preliminary evidence suggests that OTUB1 plays a specific role in the regulation of antigen responsiveness of T lymphocytes. Insights into this process could have important implications for our understanding of immune-modulation, and may identify OTU containing proteins as novel therapeutic targets.

Work over the last 25 years has established the importance of regulating protein ubiquitylation in a wide range of cellular functions including cell cycle control, transcriptional regulation, and diverse aspects of cell signaling. These processes are disturbed in many human diseases such as cancer, neurodegeneration and immunological disorders involving abnormal accumulations of proteins in cells. So far, most analyses have focused on mechanisms controlling ubiquitin ligation. However, the recognition of extensive classes of deubiquitylating enzymes (DUBs) strongly suggests a regulatory (as opposed to purely recycling) role for DUBs. Thus it is anticipated that the planned analysis of one class of these enzymes would shed light on important and medically relevant aspects of cellular physiology. A novel class of these enzymes containing an ovarian tumor domain (OTU), which encodes for a putative ubiquitin-specific cysteine protease, has been recently identified. This domain is conserved throughout evolution. Obubain 1 (OTU1), a member of this protein family, does not contribute to the deubiquitylation of the bulk of cytosolic proteins. Preliminary evidence suggests that OTU1 plays a specific role in the regulation of antigen responsiveness of T lymphocytes. Further evaluation of this phenomenon will not only shed light on the role of ubiquitin-linked mechanisms in signaling in general, but also on how these proteins may regulate the T cell signaling cascade in particular. Insights into this process could have important implications for our understanding of immune-modulation, and may identify OTU containing proteins as novel therapeutic targets.