A widely distributed family of eukaryotic and bacterial deubiquitinases related to herpesviral large tegument proteins

Abstract

Distinct families of eukaryotic deubiquitinases (DUBs) are regulators of ubiquitin signaling. Here, we report on the presence of an additional DUB class broadly distributed in eukaryotes and several bacteria. The only described members of this family are the large tegument proteins of herpesviruses, which are attached to the outside of the viral capsid. By using a bioinformatics screen, we have identified distant homologs of this VTD (Viral tegument-like DUB) family in vertebrate transposons, fungi, insects, nematodes, cnidaria, protists and bacteria. While some VTD activities resemble viral tegument DUBs in that they favor K48-linked ubiquitin chains, other members are highly specific for K6- or K63-linked ubiquitin chains. The crystal structures of K48- and K6-specific members reveal considerable differences in ubiquitin recognition. The VTD family likely evolved from non-DUB proteases and spread through transposons, many of which became ‘domesticated’, giving rise to the Drosophila male sterile (3)76Ca gene and several nematode genes with male-specific expression.

Unexpected functional and structural diversity in deubiquitinases of the Chlamydia-like bacterium Simkania negevensis

“…5). Thus, SnVTD shares the activity pro le of its W. chondrophila homolog WcVTD, which also shows K6speci city 31 .…”

“…1b). A further S. negevensis DUB candidate was closely related to members of the newly described VTD (Viral tegument-like deubiquitinase) family 31 . The entire catalytic domain and all active site residues are conserved in SNE_A13000/SnVTD.…”

“…The entire catalytic domain and all active site residues are conserved in SNE_A13000/SnVTD. Due do their inverted active site, VTD deubiquitinases do not rely on aromatic gatekeeper residues 31 (Supplementary Fig. 1c).…”

“…The S. negevensis genome codes for a single member of the recently established VTD family (Viral Tegument-like Deubiquitinases), which is present in many eukaryotes, but also contains two members in the Chlamydia-like bacterium Waddlia chondrophila 31 . Since the Simkania VTD enzyme (SnVTD) has an N-terminal membrane-spanning domain (Fig 3a) and could not be expressed in soluble form, we analyzed the fragment SnVTD for its DUB activity.…”

“…Overall, we identi ed twelve Simkania DUB candidates and found deubiquitinating activity for eight of them. Interestingly, Simkania possesses DUB families not commonly observed in bacteria, including three USP-type deubiquitinases, two members of the Josephin family and one member of the recently identi ed VTD (viral-tegument like deubiquitinase) family 31 . Like L. pneumophila, S. negevensis possesses strictly K6-and M1-speci c DUBs, although they belong to different classes and appear to be independent acquisitions from their eukaryotic hosts.…”