Ubiquitin‐specific protease‐like 1 (USPL1) is a SUMO isopeptidase with essential, non‐catalytic functions

Abstract

Isopeptidases are essential regulators of protein ubiquitination and sumoylation. However, only two families of SUMO isopeptidases are at present known. Here, we report an activity-based search with the suicide inhibitor haemagglutinin (HA)-SUMOvinylmethylester that led to the identification of a surprising new SUMO protease, ubiquitin-specific protease-like 1 (USPL1). Indeed, USPL1 neither binds nor cleaves ubiquitin, but is a potent SUMO isopeptidase both in vitro and in cells. C13orf22l-an essential but distant zebrafish homologue of USPL1-also acts on SUMO, indicating functional conservation. We have identified invariant USPL1 residues required for SUMO binding and cleavage. USPL1 is a low-abundance protein that colocalizes with coilin in Cajal bodies. Its depletion does not affect global sumoylation, but causes striking coilin mislocalization and impairs cell proliferation, functions that are not dependent on USPL1 catalytic activity. Thus, USPL1 represents a third type of SUMO protease, with essential functions in Cajal body biology.Keywords: SUMO protease; ubiquitin-specific protease family; USPL1; zebrafish C13orf22l; Cajal body EMBO reports (2012) 13, 930-938.

Deubiquitylases From Genes to Organism

“…In general, while the USP family of proteins displays variations in k cat and K m over orders of magnitude, they exhibit little specificity for particular isopeptide chain linkages (67,123). Notable exceptions are provided by USPL1 which is a SUMO-specific protease (230), USP18 which may be specific for the ubiquitin-like modifier, ISG15 (164) and CYLD which shows a marked preference for the open conformation presented by Lys63 and linear ubiquitin chains (27,123). The ubiquitin binding site of USP family enzymes such as USP21 contact Lys6, which precludes endoactivity for Lys6-linked chains.…”

“…Enzymes indicated by (*) are predicted to be inactive based on sequence or structural (PRPF8) analysis. Note that EIF3F has been proposed to deubiquitylate Notch (178) and USPL1 is a SUMO-specific protease (230). DUBs FROM GENES TO ORGANISM Table 1.…”

Structural insights into the SENP6 Loop1 structure in complex with SUMO2

“…[12][13][14] However, recently two new SUMO proteases have been identified in humans not belonging to the SENP/ULP family, desumoylating isopeptidase 1 & 2 (DESI 1 & 2) and ubiquitin-specific protease-like 1 (USPL1). 15,16 Sequence comparison of the conserved cysteine protease catalytic domain can divide the SENP/ULP family into two subgroups: one containing ULP1 (SENP1, SENP2, SENP3, and SENP5); and one containing ULP2 (SENP6 and SENP7). 13 The second group consists of proteins containing long amino acid insertions within their catalytic domains, such as in the case of human SENP6 and SENP7, whose catalytic domains contain 150 and 50 amino acid residue inserts, respectively.…”

Exploring the association between genetic variation in the SUMO isopeptidase gene USPL1 and breast cancer through integration of data from the population‐based GENICA study and external genetic databases

“…We selected three nonsynonymous coding single nucleotide polymorphisms (SNPs) in USPL1 (rs3742303 in exon 7, rs17609459 and rs7984952 in exon 9), which are implicated in amino acid exchanges from proline to serine at position 384, alanine to proline at position 522 and leucine to serine at position 531, respectively. These residues are located close or within the catalytic USPL1's protein domain, 7 a reason why these substitutions may be of functional significance. The genotyping analysis was performed in 1,021 breast cancer cases and 1,015 population-based controls from the German GENICA study.…”

“…6 Amongst these is the recently discovered SUMO isopeptidase USPL1. 7 USPL1 is a cysteine protease of the Ubiquitin-specific protease (USP) family, yet is specific for SUMO. It resides in Cajal bodies (CBs), dynamic nuclear structures involved in numerous nuclear functions ranging from maturation of snRNPs to telomere integrity, and is essential both for CB integrity and for cell proliferation.…”