Interaction with the Bardet-Biedl Gene Product TRIM32/BBS11 Modifies the Half-Life and Localization of Glis2/NPHP7 [Protein Synthesis and Degradation]

February 5th, 2014 by Ramachandran, H., Schafer, T., Kim, Y., Herfurth, K., Hoff, S., Lienkamp, S. S., Kramer–Zucker, A., Walz, G.

Although the two ciliopathies, Bardet-Biedl syndrome (BBS) and nephronophthisis (NPH) share multiple clinical manifestations, the molecular basis for this overlap remains largely unknown. Both BBS11 and NPHP7 are unusual members of their respective gene families. While BBS11/TRIM32 represents a RING finger E3 ubiquitin ligase also involved in hereditary forms of muscular dystrophy, NPHP7/Glis2 is a Gli-like transcriptional repressor that localizes to the nucleus, deviating from the ciliary localization of most other ciliopathy-associated gene products. We found that BBS11/TRIM32 and NPHP7/Glis2 can physically interact with each other, suggesting that both proteins form a functionally relevant protein complex in vivo. This hypothesis was further supported by the genetic interaction and synergist cyst formation in the zebrafish pronephros model. However, contrary to our expectation, the E3 ubiquitin ligase BBS11/TRIM32 was not responsible for the short half-life of NPHP7/Glis2, but instead promoted the accumulation of mixed K48/K63-polyubiquitylated NPHP7/Glis2 species. This modification not only prolonged the half-life of NPHP7/Glis2, but also altered the sub-nuclear localization and the transcriptional activity of NPHP7/Glis2. Thus, physical and functional interactions between NPHP and BBS gene products, demonstrated for Glis2 and TRIM32, may help to explain the phenotypic similarities between these two syndromes.
  • Posted in Journal of Biological Chemistry, Publications
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