PPPDE1 is a novel deubiquitinase belonging to a cysteine isopeptidase family

•PPPDE1 has deubiquitinating activity against K48 and K63 conjugated polyubiquitin.•PPPDE protein family is a novel cysteine deubiquitinase family.•PPPDE1 interacts with RPS7 and mediates the ubiquitin chain editing of RPS7.•PPPDE1 promotes the stabilization of RPS7.

Ubiquitinlation of proteins is prevalent and important in both normal and pathological cellular processes. Deubiquitinating enzymes (DUBs) can remove the ubiquitin tags on substrate proteins and dynamically regulate the ubiquitination process. The PPPDE family proteins were predicted to be a novel class of deubiquitinating peptidase, but this has not yet been experimentally proved. Here we validated the deubiquitinating activity of PPPDE1 and revealed its isopeptidase activity against ubiquitin conjugated through Lys 48 and Lys 63. We also identified ribosomal protein S7, RPS7, as a substrate protein of PPPDE1. Moreover, PPPDE1 could mediate the ubiquitin chain editing of RPS7, deubiquitinating Lys 48-linked ubiquitination, and finally stabilize RPS7 proteins. Taken together, we report that PPPDE1 is a novel deubiquitinase that belongs to a cysteine isopeptidase family.