Protein ubiquitylation is an important post-translational modification that regulates many critical intracellular processes. Deubiquitylating enzymes (DUBs) reverse ubiquitylation. DUBs show a surprisingly low diversity given the abundance of ubiquitin-targeted sites in the cell, and are poorly characterized. In their Research Article (Leznicki et al., 2018), Yogesh Kulathu, Pawel Leznicki and colleagues analysed a dataset of ribosome-associated transcripts and identified ∼300 protein-coding transcripts for DUBs. By taking the DUB USP35 as an example, they show that whereas USP35 isoform 1 is a soluble protein that inhibits TNF-related apoptosis-inducing ligand (TRAIL) and staurosporine-induced apoptosis, USP35 isoform 2 resides at the membrane of the endoplasmic reticulum and further localizes to lipid droplets. Overexpression of USP35 isoform 2 leads to apoptosis and ER stress, which can be blocked by inhibiting cholesterol biosynthesis. Thus, these different USP35 isoforms show distinct localization and functions in the cell. With this work, the authors extend the knowledge of the diversity of DUBs and show the importance of studying DUB isoforms to understand DUB functionality in cell physiology.
