Universität zu Köln

Esmaillie, Reza (2020). Activation of hypoxia-inducible factor signaling modulates the RNA protein interactome in Caenorhabditis elegans. PhD thesis, Universität zu Köln.

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Abstract

Acute kidney injury (AKI) shows a rising incidence especially in the elderly above the age of 65. AKI does not only lead to an acute impairment of renal function but also comes with a strongly increased risk of adverse outcome including mortality. Since there are no therapies for AKI prevention measures this would be of utmost importance. However, clinically established specific interventions protecting the kidney are not available. Prevention of kidney damage can be addressed by the concept of preconditioning which exploits the fact that damaging stimuli at a sublethal dose can activate cellular protection programs that increase resistance to future stressors. One of these preconditioning protocols is based on the activation of the hypoxia signaling pathway which has been shown to prevent AKI in animal models. However, the underlying mechanisms are still unknown hampering translation to the clinical setting. A recent study highlighted the importance of RNA binding proteins (RBPs) and hinted towards differences in RNA-protein binding upon exposure to hypoxia. In the last decade, the list of known and putative RBPs has been increasing in size and complexity across species. Thanks to the development of techniques that allow crosslinking of RNA to interacting proteins followed by both RNA pulldown and mass spectrometry (RNA interactome capture). However, little is still known about the molecular function of many RBPs and their global dynamics in different conditions. In this study, we chose C. elegans as a model organism to further dissect the complex biological question of (1) how hypoxia-inducible factor signaling modulates the RNA protein interactome and (2) how these RBPs may impact on stress resistance. Performing RNA interactome capture in wild-type and vhl-1 mutant worms we identified 1354 RBPs 270 out of which had not been described before. Among these, we found 30 RBPs to be overrepresented in vhl-1 mutant and 50 RBPs in wild-type worms. A comparison of the proteome in both strains showed that all but one of these are not differentially regulated on the level of protein abundance pointing towards differences in RNA-binding capacity. Lifespan extension in the nematode reflects increased stress resistance. To enable screening of this phenotype after knockdown of RBP candidates in C. elegans, we established the automated lifespan machine. Using this approach, we could show longevity induced by knockdown several of these RBPs. Our results will significantly add to the understanding of the RBPome in the nematode and its modulation by HIF-signaling.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Esmaillie, Reza resmaill@smail.uni-koeln.de UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-251529
Date:	2020
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language RBP, Hypoxia English
Date of oral exam:	30 October 2020
Referee:	Name Academic Title Müller, Roman-Ulrich Prof. Dr. Schwarz, Günter Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25152