Abstract
A20 is a ubiquitin-editing enzyme that is known to regulate inflammatory signaling and cell death. However, A20 mutations are also frequently found in multiple malignancies suggesting a potential role as a tumor suppressor as well. We recently described a novel role for A20 in regulating the wnt-beta-catenin signaling pathway and suppressing colonic tumor development in mice. The underlying mechanisms for this phenomenon are unclear. To study this, we first generated A20 knockout cell lines by genome-editing techniques. Using these cells, we show that loss of A20 causes dysregulation of wnt-dependent gene expression by RNAseq. Mechanistically, A20 interacts with a proximal signaling component of the wnt-signaling pathway, receptor interacting protein kinase 4 (RIPK4), and regulation of wnt-signaling by A20 occurs through RIPK4. Finally, similar to the mechanism by which A20 regulates other members of the receptor interacting protein kinase family, A20 modifies ubiquitin chains on RIPK4 suggesting a possible molecular mechanism for A20’s control over the wnt-signaling pathway.
Highlights
Tumor necrosis factor alpha induced protein 3 (TNFAIP3), known as A20, is a ubiquitin editing enzyme with well-known functions regulating inflammatory signaling and cell death downstream of the TNF-receptor superfamily [1]
We show for the first time that A20 interacts with receptor interacting protein kinase 4 (RIPK4) and that the regulation of wnt-signaling by A20 is dependent on RIPK4
We previously demonstrated that A20 siRNA knockdown enhanced canonical wnt-signaling in a colon cancer cell line, RKO, with intact beta-catenin signaling [26]
Summary
Tumor necrosis factor alpha induced protein 3 (TNFAIP3), known as A20, is a ubiquitin editing enzyme with well-known functions regulating inflammatory signaling and cell death downstream of the TNF-receptor superfamily [1]. Absence of this critical negative regulatory protein recapitulates the phenotype of many inflammatory diseases in mice [2] and loss of function mutations leads to severe auto-inflammatory disease in humans [3]. A20 can remove K63-linked ubiquitin moieties through an ovarian tumor-like domain, while the fourth zinc finger has ubiquitin E3-ligase activity and can add K48-linked ubiquitin chains to proteins promoting their proteasome-dependent degradation.
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