title: Interaction with the Bardet-Biedl gene product TRIM32/BBS11 modifies the half-life and localization of Glis2/NPHP7.
abstract: 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 Lys(48)/Lys(63)-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.
authors: From the Department of Medicine, Renal Division, University of Freiburg Medical Center, 79106 Freiburg, Germany.
authors: Haribaskar
authors: H
authors: Ramachandran
authors: Tobias
authors: T
authors: Schäfer
authors: Yunhee
authors: Y
authors: Kim
authors: Konstantin
authors: K
authors: Herfurth
authors: Sylvia
authors: S
authors: Hoff
authors: Soeren S
authors: SS
authors: Lienkamp
authors: Albrecht
authors: A
authors: Kramer-Zucker
authors: Gerd
authors: G
authors: Walz
mesh_terms: D000818:Animals; D020788:Bardet-Biedl Syndrome / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D060066:Protein Interaction Maps; D021381:Protein Transport; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D015027:Zebrafish
chemical_list: C447919:GLIS2 protein, human; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; C094027:TRIM32 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Bardet-Biedl Syndrome; Ciliopathies; Genetic Diseases; Nephronophthisis; Protein Degradation; Protein Stability; Transcription Regulation; Ubiquitylation