Dr. Débora B. Trentini Schmidt

Associated Principal Investigator, assoc. Junior Research Group 05 CMMC

Dr. Débora B. Trentini Schmidt

assoc. Junior Research Group 05 ZMMK

+49 221 478-42566


Center for Molecular Medicine Cologne (CMMC)

Robert-Koch-Str. 21

50937 Köln

The homeostasis of the cellular proteome (proteostasis) involves a large number of intricate cellular pathways working on the generation of functional proteins (biosynthesis and folding), prevention of protein damage (conformational maintenance), and removal of defective proteins (degradation). Misfolded proteins are not only dysfunctional, but they can also form potentially toxic aggregates that represent a hallmark of many aging-associated neurodegenerative diseases. The focus of our research is to understand how proteostasis pathways distinguish between defective and functional proteins, and how human cells deal with the buildup of potentially harmful protein species during stress.

Our research: Human cells express more than 10,000 different proteins. To fulfill their functions, proteins must be correctly synthesized, folded into appropriate three-dimensional structures, assembled into macromolecular complexes, and localized to specific cellular compartments. Mistakes can occur during any of these steps, resulting in a myriad of different defective protein species. Moreover, many proteins are susceptible to damage by endogenous and environmental stresses, given the dynamic and often unstable nature of protein structures. Our research aims at understanding how protein quality control pathways recognize and deal with different types of defective proteins, despite the huge complexity of the proteome. Moreover, we want to study how cells adapt to proteotoxic stress, and how the disruption of proteostasis pathways can lead to cellular toxicity and eventually to disease.

Our goals: Our main objective is to elucidate specificity mechanisms of protein quality control. We want to characterize the division of labor between different protein quality control pathways by identifying the endogenous substrates of key proteostasis players, such as E3 ubiquitin ligases. The goal is to use this information to predict and experimentally test the determinants of substrate selection. In addition, we want to characterize the cellular consequences upon the ablation of specific proteostasis factors, and to analyze their regulation upon proteotoxic stress. The long-term vision is to contribute to the understanding of the pathological states established upon age-dependent decline in proteostasis capacity and to pinpoint potential targets of therapy.

Our successes: Prior to establishing her group, Dr. Trentini identified the physiological substrates of the ribosome-associated quality control (RQC) pathway in human cells. This pathway is recruited to ribosomes that stalled during translation and serves to target the nascent polypeptides produced by these failed translation events for degradation. Our study showed that RQC-mediated degradation is independent of the folding state of the stalled substrates, which distinguishes RQC from canonical quality control pathways that rely on structural cues for targeting. In addition, we identified gene/protein traits associated with increased risk of RQC-mediated degradation, such as: long sequences, tendency towards premature polyadenylation, and large numbers of transmembrane domains.

Our methods/techniques: We use advanced mass spectrometry methods in combination with bioinformatics analysis to globally characterize proteostasis responses. For mechanistic studies, we employ a combination of biochemical, fluorescence-based, and chemical-biology methods, using human cell culture models generated by CRISPR-Cas technology.


Figure 1: The proteostasis network. Molecular chaperones assist the conformational folding of proteins, guiding them along the proper folding pathway and preventing non-specific associations that can cause protein aggregation. When this process fails, protein aggregation can still be prevented by the targeted destruction of misfolded/defective proteins by the ubiquitin-proteasome system or by the autophagy process. A number of stresses ensued from metabolic, environmental, and pathological conditions can cause metastable proteins to unfold, increasing the burden upon the proteostasis network.

Figure 2: Generation of defective protein products during protein biogenesis. The synthesis of functional, stable proteins comprises multiple steps (left column). Errors at the early steps (RNA maturation, ribosomal decoding, and possibly membrane insertion) result in ribosomal stalling, which serves as a signal for the recruitment of the ribosome-associated quality control pathway (RQC) to degrade the stalled nascent chains. Failures during the protein folding and assembly steps as well as mature protein damage, are sensed by a large number of quality control pathways relying on structural cues to select proteins for degradation. Figure adapted from Trentini et al. PNAS. 2020; 117(8):4099-4108.