Interaction with the Bardet-Biedl Gene Product TRIM32/BBS11 Modifies the Half-life and Localization of Glis2/NPHP7

Ramachandran, Haribaskar; Schäfer, Tobias; Kim, Yun-Hee; Herfurth, Konstantin; Hoff, Sylvia; Lienkamp, Soeren S.; Kramer-Zucker, Albrecht; Walz, Gerd

doi:10.1074/jbc.m113.534024

Cited by 18 publications

(24 citation statements)

References 51 publications

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“…However, contrarily to what was expected BBS11 is responsible for the accumulation of polyubiquitylated NPHP7 species, a modification that prolonged the half-life of NPHP7 and also altered its sub-nuclear localization and transcriptional activity. Thus, the authors propose that this interaction may help explain the phenotypic similarities between these two ciliopathies [93]. It was reported that BBS11/TRIM32 can ubiquitinate actin and downregulate its levels upon overexpression in Hek293 cells [94], findings that might be relevant to link this protein with ciliogenesis as we will discuss next.…”

Section: Regulation Of Proteasome Activitymentioning

confidence: 99%

Bardet–Biedl syndrome: Is it only cilia dysfunction?

et al. 2015

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a b s t r a c tBardet-Biedl syndrome (BBS) is a genetically heterogeneous, pleiotropic disorder, characterized by both congenital and late onset defects. From the analysis of the mutational burden in patients to the functional characterization of the BBS proteins, this syndrome has become a model for both understanding oligogenic patterns of inheritance and the biology of a particular cellular organelle: the primary cilium. Here we briefly review the genetics of BBS to then focus on the function of the BBS proteins, not only in the context of the cilium but also highlighting potential extra-ciliary roles that could be relevant to the etiology of the disorder. Finally, we provide an overview of how the study of this rare syndrome has contributed to the understanding of cilia biology and how this knowledge has informed on the cellular basis of different clinical manifestations that characterize BBS and the ciliopathies.

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Section: Regulation Of Proteasome Activitymentioning

confidence: 99%

Bardet–Biedl syndrome: Is it only cilia dysfunction?

et al. 2015

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“…Since Glis2/NPHP7 is ubiquitylated and targeted for proteasomal degradation [16], a short half-life and low protein levels may account for this problem. To further investigate the regulation of Glis2/NPHP7 proteins levels, we investigated whether Glis2/NPHP7 is modified by SUMOylation in addition to ubiquitylation.…”

Section: Introductionmentioning

confidence: 99%

SUMOylation Blocks the Ubiquitin-Mediated Degradation of the Nephronophthisis Gene Product Glis2/NPHP7

et al. 2015

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Glis2/NPHP7 is a transcriptional regulator mutated in type 7 nephronophthisis, an autosomal recessive ciliopathy associated with cystic and fibrotic kidney disease as well as characteristic extrarenal manifestations. While most ciliopathy-associated molecules are found in the cilium, Glis2/NPHP7 presumably localizes to the nucleus. However, the detection of endogenous Glis2/NPHP7 has remained unsuccessful, potentially due to its ubiquitylation-dependent rapid degradation. We report now that Glis2/NPHP7 is also SUMOylated, preferentially by PIAS4, which conjugates Glis2/NPHP7 to SUMO3. SUMOylation interferes with ubiquitylation and degradation of Glis2/NPHP7, suggesting that Glis2/NPHP7 protein levels are regulated by competing ubiquitylation/ SUMOylation. SUMOylation also alters the transcriptional activity of Glis2/NPHP7. While Glis2/NPHP7 activates the mouse insulin-2-promotor (mIns2), SUMOylated Glis2/NPHP7 lacks this property, and seems to act as a repressor. Taken together, our data reveal that Glis2/NPHP7 is extensively modified by post-translational modifications, suggesting that a tight control of this transcriptional regulator is required for normal development and tissue homeostasis.

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“…Both GLIS2 and GLIS3 have been reported to be ubiquitinated and sumoylated [9, 34, 35]. Yeast two-hybrid and mass spectrometric analysis revealed that a number of WW-domain containing HECT E3 ubiquitin ligases, including ITCH, NEDD4, and SMURF1/2, interact with GLIS3 [9, 26].…”

Section: Transcriptional Activity and Protein Interactionsmentioning

confidence: 99%

“…GLIS2 was found to interact with the E3 ubiquitin ligase, Tripartite Motif Containing 32 (TRIM32, also named Bardet-Biedl Syndrome 11 or BBS11), and BBS1 [35, 36], proteins that are part of the Bardet-Biedl syndrome (BSS) multiprotein complex, which plays a role in ciliogenesis and cilia maintenance. In zebrafish, deficiency in either TRIM32 or GLIS2 leads to the development of renal cysts.…”

Section: Transcriptional Activity and Protein Interactionsmentioning

confidence: 99%

“…TRIM32 also modifies GLIS2 transcriptional activity; it reversed the inhibition of β-catenin-mediated transcriptional activation by GLIS2 and inhibited the GLIS2-induced activation of the Ins2 promoter. In addition, TRIM32 changes the subnuclear localization of GLIS2 and instead of a diffuse pattern of expression it becomes localized to nuclear bodies [35], including PML bodies, which are involved in the regulation of multiple cellular functions, such as apoptosis, DNA repair, and cell cycle [37]. where it interacts with.…”

Section: Transcriptional Activity and Protein Interactionsmentioning

confidence: 99%

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GLIS1–3 transcription factors: critical roles in the regulation of multiple physiological processes and diseases

Jetten

2018

Cell. Mol. Life Sci.

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Krüppel-like zinc finger proteins form one of the largest families of transcription factors. They function as key regulators of embryonic development and a wide range of other physiological processes, and are implicated in a variety of pathologies. GLI-Similar 1–3 (GLIS1–3) constitute a subfamily of Krüppel-like zinc finger proteins that act either as activators or repressors of gene transcription. GLIS3 plays a critical role in the regulation of multiple biological processes and is a key regulator of pancreatic β cell generation and maturation, insulin gene expression, thyroid hormone biosynthesis, spermatogenesis, and the maintenance of normal kidney functions. Loss of GLIS3 function in humans and mice leads to the development of several pathologies, including neonatal diabetes and congenital hypothyroidism, polycystic kidney disease, and infertility. Single nucleotide polymorphisms in GLIS3 genes have been associated with increased risk of several diseases, including type 1 and type 2 diabetes, glaucoma, and neurological disorders. GLIS2 plays a critical role in the kidney and GLIS2 dysfunction leads to nephronophthisis, an end-stage, cystic renal disease. In addition, GLIS1–3 have regulatory functions in several stem/progenitor cell populations. GLIS1 and GLIS3 greatly enhance reprogramming efficiency of somatic cells into induced embryonic stem cells, while GLIS2 inhibits reprogramming. Recent studies have obtained substantial mechanistic insights into several physiological processes regulated by GLIS2 and GLIS3, while little is still known about the physiological functions of GLIS1. The localization of some GLIS proteins to the primary cilium suggests that their activity may be regulated by a downstream primary cilium-associated signaling pathway. Insights into the upstream GLIS signaling pathway may provide opportunities for the development of new therapeutic strategies for diabetes, hypothyroidism, and other diseases.

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Interaction with the Bardet-Biedl Gene Product TRIM32/BBS11 Modifies the Half-life and Localization of Glis2/NPHP7

Cited by 18 publications

References 51 publications

Bardet–Biedl syndrome: Is it only cilia dysfunction?

Bardet–Biedl syndrome: Is it only cilia dysfunction?

SUMOylation Blocks the Ubiquitin-Mediated Degradation of the Nephronophthisis Gene Product Glis2/NPHP7

GLIS1–3 transcription factors: critical roles in the regulation of multiple physiological processes and diseases

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