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Mapping the interactome of HPV E6 and E7 oncoproteins with the ubiquitin‐proteasome system
Author(s) -
Poirson Juline,
Biquand Elise,
Straub MarieLaure,
Cassonnet Patricia,
Nominé Yves,
Jones Louis,
Werf Sylvie,
Travé Gilles,
Zanier Katia,
Jacob Yves,
Demeret Caroline,
Masson Murielle
Publication year - 2017
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14193
Subject(s) - ubiquitin ligase , ubiquitin , cullin , ubiquitin protein ligases , proteasome , deubiquitinating enzyme , biology , microbiology and biotechnology , scaffold protein , chemistry , biochemistry , gene , signal transduction
Protein ubiquitination and its reverse reaction, deubiquitination, regulate protein stability, protein binding activity, and their subcellular localization. These reactions are catalyzed by the enzymes E1, E2, and E3 ubiquitin (Ub) ligases and deubiquitinases (DUBs). The Ub‐proteasome system (UPS) is targeted by viruses for the sake of their replication and to escape host immune response. To identify novel partners of human papillomavirus 16 ( HPV 16) E6 and E7 proteins, we assembled and screened a library of 590 cDNA s related to the UPS by using the Gaussia princeps luciferase protein complementation assay. HPV 16 E6 was found to bind to the homology to E6AP C terminus‐type Ub ligase (E6AP), three really interesting new gene ( RING )‐type Ub ligases ( MGRN 1, LNX 3, LNX 4), and the DUB Ub‐specific protease 15 (USP15). Except for E6 AP , the binding of UPS factors did not require the Lxx LL ‐binding pocket of HPV 16 E6. LNX 3 bound preferentially to all high‐risk mucosal HPV E6 tested, whereas LNX 4 bound specifically to HPV 16 E6. HPV 16 E7 was found to bind to several broad‐complex tramtrack and bric‐a‐brac domain‐containing proteins (such as TNFAIP 1/ KCTD 13) that are potential substrate adaptors of Cullin 3‐ RING Ub ligases, to RING ‐type Ub ligases implicated in innate immunity ( RNF 135, TRIM 32, TRAF 2, TRAF 5), to the substrate adaptor DCAF 15 of Cullin 4‐ RING Ub ligase and to some DUBs ( USP 29, USP 33). The binding to UPS factors did not require the LxCxE motif but rather the C‐terminal region of HPV 16 E7 protein. The identified UPS factors interacted with most of E7 proteins across different HPV types. This study establishes a strategy for the rapid identification of interactions between host or pathogen proteins and the human ubiquitination system.