XAF1 antagonizes TRIM28 activity through the assembly of a ZNF313-mediated destruction complex to suppress tumor malignancy.

Publisher: Springer Singapore Country of Publication: Singapore NLM ID: 9918283581406676 Publication Model: Electronic Cited Medium: Internet ISSN: 2662-8651 (Electronic) Linking ISSN: 26628651 NLM ISO Abbreviation: Mol Biomed Subsets: MEDLINE

Original Publication: Singapore : Springer Singapore, [2020]-

Ubiquitination* ; Tripartite Motif-Containing Protein 28*/metabolism ; Tripartite Motif-Containing Protein 28*/genetics ; Apoptosis Regulatory Proteins*/metabolism ; Apoptosis Regulatory Proteins*/genetics ; Adaptor Proteins, Signal Transducing*/metabolism ; Adaptor Proteins, Signal Transducing*/genetics ; Intracellular Signaling Peptides and Proteins*/metabolism ; Intracellular Signaling Peptides and Proteins*/genetics; Humans ; Animals ; Cell Line, Tumor ; Mice ; Neoplasm Proteins/metabolism ; Neoplasm Proteins/genetics ; Apoptosis ; Epithelial-Mesenchymal Transition/genetics ; Cell Proliferation ; Tumor Suppressor Protein p53/metabolism ; Tumor Suppressor Protein p53/genetics ; Cell Movement ; Neoplasms/genetics ; Neoplasms/pathology ; Neoplasms/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitin-Protein Ligases/genetics ; HEK293 Cells ; Protein Binding ; Mice, Nude

X-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a stress-inducible pro-apoptotic protein that is commonly inactivated in multiple human cancers. Nevertheless, the molecular basis for its tumor suppression function remains largely uncharacterized. Here we report that XAF1 antagonizes the oncogenic activity of tripartite motif containing 28 (TRIM28) ubiquitin E3 ligase through zinc finger protein 313 (ZNF313)-induced ubiquitination and proteasomal degradation. XAF1 exerts apoptosis-promoting effect more strongly in TRIM28 ^+/+ versus XAF1 ^-/- tumor cells and suppresses tumor cell growth, migration, invasion, and epithelial-to-mesenchymal transition and xenograft tumor growth in a highly TRIM28-dependent fashion. Mechanistically, XAF1 interacts directly with the RING domains of TRIM28 and ZNF313 through the ZF6 and ZF7 domain, respectively, thereby facilitating ZNF313 interaction with and ubiquitination of TRIM28. A mutant XAF1 lacking either ZF6 or ZF7 domain exhibits no activity to promote TRIM28 ubiquitination. By destabilizing TRIM28, XAF1 blocks TRIM28-driven ubiquitination of p53 and RLIM, p53-HDAC1 interaction, and TWIST1 stabilization. Intriguingly, TRIM28 destabilizes XAF1 through K48-linked polyubiquitination and proteasomal degradation to protect tumor cells from apoptotic stress, indicating its role as an intrinsic antagonist against XAF1 and the antagonistic interplay of XAF1 and TRIM28. XAF1 expression is inversely correlated with TRIM28 expression in cancer cell lines and tumor tissues and more tightly associated with the survival of TRIM28-high versus TRIM28-low patients. Together, this study uncovers a novel mechanism by which XAF1 suppresses tumor malignancy and an important role for XAF1-TRIM28 interplay in governing stress response, illuminating the mechanistic consequence of its alteration during tumorigenic process.
Competing Interests: Declarations Ethics approval and consent to participate This study was carried out in line with the principles of the Declaration of Helsinki. All animal studies were performed with the approval of Korea University Institutional Animal Care and Use Committee (KUIACUC 2021–0044)) and Korea Animal Protection Law. Consent for publication Not applicable. Competing interests The authors have no relevant financial or non-financial interests to disclose.
(© 2024. The Author(s).)

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RS-2024-00356020 National Research Foundation of Korea; K2120681 Korea University

Keywords: TRIM28; Tumor suppression; Ubiquitination; XAF1; ZNF313

EC 2.3.2.27 (Tripartite Motif-Containing Protein 28)
0 (XAF1 protein, human)
0 (Apoptosis Regulatory Proteins)
0 (Adaptor Proteins, Signal Transducing)
EC 2.3.2.27 (TRIM28 protein, human)
0 (Intracellular Signaling Peptides and Proteins)
0 (Neoplasm Proteins)
0 (Tumor Suppressor Protein p53)
EC 2.3.2.27 (RLIM protein, human)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)

Date Created: 20241112 Date Completed: 20241112 Latest Revision: 20241116

20241116

PMC11557793

10.1186/s43556-024-00224-9

39532800