Mammalian and bacterial adaptors function as co-disinhibitory pairs to activate the E3 ubiquitin ligase WWP2
File(s)
Published version
Accepted version
Author(s)
Type
Journal Article
Abstract
The NEDD4-like E3 ubiquitin ligase, WWP2, is involved in a range of host processes from cell differentiation to T cell immunity. Ligase activity is tightly regulated with WWP2 being held in an autoinhibited state. Binding of a PY motif-containing adaptor, an Ndfip, via the WW domains of NEDD4-like E3 ubiquitin ligases leads to their disinhibition. Here, we show that the canonical Ndfip, NDFIP2, requires multiple PY motifs for interaction with and activation of WWP2. In contrast, the single PY-motif containing Ndfips TMEM127 and SUSD6 function as a co-disinhibitory pair. TMEM127 and the Salmonella protein SteD also function as a co-disinhibitory pair. However, SteD requires a different region of WWP2, the C2 domain, for interaction with WWP2 and this interaction results in disinhibition of WWP2. These findings demonstrate a range of ways that Ndfips can disinhibit WWP2. To our knowledge, these are the first examples of two Ndfips functioning as co-disinhibitory pairs, and of a bacterial effector that disinhibits an E3 ubiquitin ligase.
Date Issued
2025-12-01
Date Acceptance
2025-09-26
Citation
Journal of Biological Chemistry, 2025, 301 (12)
ISSN
0021-9258
Publisher
Elsevier BV
Journal / Book Title
Journal of Biological Chemistry
Volume
301
Issue
12
Copyright Statement
® 2025 The Authors. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/41135677
PII: S0021-9258(25)02699-7
Subjects
Salmonella enterica
adaptor protein/ ubiquitin
virulence factor/ E3 ubiquitin ligase
Publication Status
Published
Coverage Spatial
United States
Article Number
110847
Date Publish Online
2025-10-22