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RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling


The Wnt/β-catenin signalling pathway plays essential roles in embryonic development and adult tissue homeostasis, and deregulation of this pathway has been linked to cancer. Axin is a concentration-limiting component of the β-catenin destruction complex, and its stability is regulated by tankyrase. However, the molecular mechanism by which tankyrase-dependent poly(ADP-ribosyl)ation (PARsylation) is coupled to ubiquitylation and degradation of axin remains undefined. Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation. Thus, identification of RNF146 as a PARsylation-directed E3 ligase establishes a molecular paradigm that links tankyrase-dependent PARsylation to ubiquitylation. RNF146-dependent protein degradation may emerge as a major mechanism by which tankyrase exerts its function.

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Figure 1: RNF146 positively regulates Wnt signalling by affecting the protein level of axin.
Figure 2: Interaction between the WWE domain and PAR is essential for RNF146-dependent regulation of axin in vivo.
Figure 3: RNF146 is required for PARsylation-dependent degradation of axin and tankyrase in vivo.
Figure 4: PARsylation-dependent ubiquitylation in vitro.
Figure 5: BLZF1 is identified as a substrate of tankyrase and RNF146 using quantitative mass spectrometry.


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We thank D. Patel, C. Xin, E. McWhinnie, S. Zhao, J. Murphy, Y. Mishina and J. Klekota for technical assistance and W. Shao, F. Stegmeier, J. Tallarico, T. Bouwmeester and M. Kirschner for comments and advice.

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Y.Z., C.M., Y.F., G.A.M., M.S., M.H., A.B., V.E.M, P.M.F., J.A.P., S-M.A.H and F.C. conceived and designed the study. Y.Z., S.L., C.M., Y.F., O.C., G.A.M., M.S., X.S. and F.C. designed and implemented experiments. Y.Z. and F.C. wrote the paper.

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Correspondence to Shih-Min A. Huang or Feng Cong.

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The authors declare no competing financial interests.

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Zhang, Y., Liu, S., Mickanin, C. et al. RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling. Nat Cell Biol 13, 623–629 (2011).

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