DS0403 -

Functional characterization of ANKS6/ANKS3/BICC1 complex and implication in cystic kidney diseases – AnBiCyst

Submission summary


Nephronophthisis (NPH) is an autosomal recessive kidney disorder characterized by chronic tubulointerstitial nephritis with massive interstitial fibrosis and cyst formation at the cortico-medullar junction. It represents a main cause of end-stage renal disease (ESRD) during infancy. NPH belongs to ciliopathies, a group of multi-systemic disorders linked to dysfunctions of the primary cilium, a sensory organelle which controls key signaling pathways during tissue development/homeostasis. Renal cystic dysplasia (RCD) is another major cause of ESRD in children which is linked to defects during kidney development and therefore causes fetal/perinatal death in the more severe forms. In addition to those two pathologies affecting children, polykystic kidney disease (PKD) is the main cause of ESRD in adults and is characterized by the presence of large cysts all along the nephrons.

Partner 1 participated to the identification of 13 of the 20 NPH causative genes known to date (NPHP1-20), most of which encode ciliary proteins. Recently, mutations habe been identified in three new genes encoding SAM domain containing proteins, ANKS6-BICC1-ANKS3, in NPH and RCD patients. Mutations of two of these genes were also identified in PKD patients (ANKS6, partner 1) as well as in two rodent PKD models (Bicc1 and Ank6, partners 2 and 3). These genetic data suggest that the products of these genes control mechanisms shared by all types of cystic kidney diseases. These three proteins interact with each other and polymerize through their SAM domains. Despite the fact that they all bind to other NPHPs, the ciliary functions of BICC1 and ANKS3 remain poorly characterized. Interestingly, BICC1 negatively control the expression of specific target mRNAs encoding for key signaling components of the ciliary membrane thanks to ts interaction with the processing bodies (PBs), cytoplasmic structures implicated in mRNA decay. Therefore, ANKS3 and ANKS6 may also regulate mRNA expression through their interaction with BICC1.
To better understand the function of ANKS3, partner 1 performed a proteomic analysis which revealed new partners for ANKS3. Among them, several are implicated in stress response including regulators of the DNA damage response signaling (DDR), whose defects were previously linked with NPH, and components of stress granules (SGs). Interestingly, SGs sequester mRNA upon stress response and established functional contacts with PBs, suggesting a functional link between ANKS3 and BICC1 in the regulation of mRNA during stress response and/or tissue homeostasis/development.

The aim of this project is to characterize the role of the ANKS3-BICC1-ANKS6 complex in the pathophysiological mechanisms of renal cystic diseases, mainly based on analysis of the effects of patient and rodent model mutations on various cellular processes and molecular pathways. The main and most original part of this proposal concerns the characterization of the role of these proteins in the regulation of mRNA expression during stress response as well as during kidney homeostasis. This will be mainly achieved through the study of the role of ANKS3 within SGs and the identification of the mRNAs targeted by BICC1 and ANKS3. This proposal is based on the preliminary results and the complementary expertise/skills of the three members of the consortium, as well as on the numerous in vitro cellular models (invalidated kidney cell lines (CRISPR), patients fibroblasts, iPSc) and in vivo models (zebrafish, mouse and rats), most of which are already available to the consortium. This project should allow identifying new mechanisms and signaling pathways commonly affected in cystic kidney diseases.

Project coordinator

Madame Sophie Saunier (Institut Imagine, Laboratoire des Maladies Rénales Héréditaires)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

UPD-IMAGINE Institut Imagine, Laboratoire des Maladies Rénales Héréditaires
INSERM DR paris 6 Institut National de la Santé et de la Recherche Médicale
University of Heidelberg University of Heidelberg

Help of the ANR 503,915 euros
Beginning and duration of the scientific project: September 2016 - 36 Months

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