Ramachandran, H., Schäfer, T., Kim, Y., Herfurth, K., Hoff, S., Lienkamp, S.S., Kramer-Zucker, A., and Walz, G. (2014) Interaction with the Bardet-Biedl Gene Product TRIM32/BBS11 Modifies the Half-life and Localization of Glis2/NPHP7. The Journal of biological chemistry. 289(12):8390-8401.
Although the two ciliopathies Bardet-Biedl syndrome and nephronophthisis 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.
Although 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 Lys48/Lys63-polyubiquitylated NPHP7/Glis2 species. This modification not only prolonged the half-life of NPHP7/Glis2, but also altered
the subnuclear localization and the transcriptional activity of NPHP7/Glis2. Thus, physical and functional interactions between
NPHP and Bardet-Biedl syndrome gene products, demonstrated for Glis2 and TRIM32, may help to explain the phenotypic similarities
between these two syndromes.