Protein quality control during ageing

1 PhD project offered in the IPP summer call 2021

This project is part of the Science of Healthy Ageing Research Programme (SHARP).

Scientific background

Ageing is associated with an accumulation of damaged proteins and toxic protein aggregates and therefore characterized by an increased demand for protein quality control (PQC) and regulated protein turnover. The two key cellular PQC systems for the timely and effective removal of misfolded, damaged or aggregated proteins are the ubiquitin-proteasome system and the autophagy-lysosome pathway. Hallmarks of cellular ageing and senescence are an enhanced lysosomal activity and an increase in selective macroautophagy pathways. However, the age-associated dynamics in the ubiquitylation process responsible for these changes, including the expression and activities of ubiquitin ligases and deubiquitylating enzymes, under baseline conditions and following autophagy induction remains poorly understood.

PhD project: Age-associated protein ubiquitylation and autophagy     

We will perform an analysis of how ubiquitylation and protein degradation is affected during cellular ageing, especially after induction of autophagy by starvation or genotoxic stress. To this end, we will employ human IMR90 cells as model for in-depth characterization of critical individual substrates and their cognate ubiquitylation factors to understand the relevance of the observed age-related alterations. The project combines the expertise of three labs in autophagy and PQC, ubiquitin signaling and quantitative mass spectrometry-based proteomics. Cell culture work and functional autophagy assays will be performed in the Behl lab, followed by analysis of the age-associated ubiquitylome and proteome in the Beli lab. Downstream analysis of the identified ubiquitylation factors and/or ubiquitylated candidate proteins will be done in the Ulrich lab in constant exchange with the Behl and Beli labs regarding translational aspects and proteomic expertise in protein-protein interaction analysis, respectively.

If you are interested in this project, please select Christian Behl as your group preference in the IPP application platform.

Publications relevant to the project

Gamerdinger M, Hajieva P, Kaya AM, Wolfrum U, Hartl FU & Behl C (2009) Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3. EMBO J, 28:889-901 Link

Hildebrandt A, Brüggemann M, Rücklé C, Boerner S, Heidelberger JB, Busch A, Hänel H, Voigt A, Möckel MM, Ebersberger S, Scholz A, Dold A, Schmid T, Ebersberger I, Roignant JY, Zarnack K, König J, Beli P (2019) The RNA-binding ubiquitin ligase MKRN1 functions in ribosome-associated quality control of poly(A) translation. Genome Biol, 20(1):216 Link

Renz C, Albanèse V, Tröster V, Albert TK, Santt O, Jacobs SC, Khmelinskii A, Léon S & Ulrich HD (2020) Ubc13-Mms2 cooperates with a family of RING E3 proteins in budding yeast membrane protein sorting. J Cell Sci, 133:244566 Link

Bekbulat F, Schmitt D, Feldmann A, Huesmann H, Eimer S, Juretschke T, Beli P, Behl C & Kern A (2020) RAB18 Loss Interferes With Lipid Droplet Catabolism and Provokes Autophagy Network Adaptations. J Mol Biol, 432:1216-1234 Link

Mizushima N and Levine B (2020) Autophagy in Human Diseases. N Engl J Med, 383:1564-1576 Link

Contact

Prof. Christian Behl (If you are interested in this project, please select Christian Behl as your group preference in the IPP application platform.)

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Prof. Petra Beli

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Prof. Helle Ulrich

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