- The spiders at the center of the web
- Csde1 and strap control translation in erythropoiesis
C.E. van der Schoot
M.M. von Lindern
P.A.C. 't Hoen
- Award date
- 26 October 2018
- Number of pages
- Document type
- PhD thesis
- Faculty of Medicine (AMC-UvA)
The production of new red blood cells (erythropoiesis) must be tightly controlled. A shortage of erythrocytes causes hypoxic damage to organs and tissue, whereas an overproduction of erythrocytes may lead to thrombosis and ischemia. Much of the control of gene expression during erythropoiesis occurs at the translational level. In this thesis, we discuss Csde1 and Strap, two proteins which are essential in regulating translation in erythropoiesis. Csde1 is an RNA-binding protein at the center of a web of overlapping regulatory pathways that may lead to either stimulation or repression of translation, depending on the transcript. We found that transcripts bound by Csde1 primarily encode proteins involved in translation initiation, ribogenesis, and protein degradation, indicating Csde1 as a meta-regulator of translation. A subset of Csde1 bound transcripts are oppositely regulated at the mRNA and protein level in cells with diminished Csde1 functionality, including the critical translational regulator Pabpc1. A protein-protein pulldown indicated that Strap is the binding partner most heavily associated with Csde1. Strap knockdown did not significantly alter the pool of transcripts associated with Csde1. However, knockdown of Strap altered expression of Csde1-associated transcripts encoding eIFs implicated in translation under hypoxic conditions. Expression of other hypoxic genes was also deregulated, suggesting possible cooperation between Csde1 and Strap during hypoxia. We implemented ribofootprinting to identify transcripts with altered translational efficiency under proteotoxic stress. Csde1 was among the transcripts with reduced translation efficiency, suggesting that translational regulation mediated by Csde1 is altered during cellular stress.
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Thesis (Embargo up to and including 26 October 2020)
5: General discussion (Embargo up to and including 26 October 2020)
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