Thorsten Hoppe

• Prof. Dr. rer nat
• Principal Investigator at University of Cologne

The UCS (UNC-45/CRO1/She4) chaperones play an evolutionarily conserved role in promoting myosin-dependent processes, including cytokinesis, endocytosis, RNA transport, and muscle development. To investigate the protein machinery orchestrating myosin folding and assembly, we performed a comprehensive analysis of Caenorhabditis elegans UNC-45. Our st...

Protein ubiquitylation is a key post-translational control mechanism contributing to different physiological processes, such as signal transduction and ageing. The size and linkage of a ubiquitin chain, which determines whether a substrate is efficiently targeted for proteasomal degradation, is determined by the interplay between ubiquitylation and...

Protein degradation in eukaryotes often requires the ubiquitin-selective chaperone p97 for substrate recruitment and ubiquitin-chain assembly. However, the physiological relevance of p97, and its role in developmental processes, remain unclear. Here, we discover an unanticipated function for CDC-48/p97 in myosin assembly and myofibril organization,...

The ubiquitin-proteasome system is crucial for proteostasis, particularly during proteotoxic stress. The interaction between heat shock protein (HSP) 70 and the ubiquitin ligase CHIP plays a key role in this process. Our study investigates the Caenorhabditis elegans orthologs HSP-1 and CHN-1, demonstrating that HSP-1 binding decreases CHN-1 E3 liga...

Mechanical stress during muscle contraction is a constant threat to proteome integrity. However, there is a lack of experimental systems to identify critical proteostasis regulators under mechanical stress conditions. Here, we present the transgenic Caenorhabditis elegans model OptIMMuS (Optogenetic Induction of Mechanical Muscle Stress) to study c...

Many proteins self-assemble into dimers and higher-order oligomers. Therefore, the goal of this protocol is to characterize the conformational states of an endogenous protein of interest. Here, we present a protocol for assessing protein self-assembly in cell lysates using chemical cross-linking. We describe steps for chemical cross-linking with re...

Most of the functions of LC3/GABARAP in macroautophagy/autophagy are considered to depend on their association with the phagophore membrane through a conjugation to a lipid. Using site-directed mutagenesis, we inhibited the conjugation of LGG-1, the single homolog of GABARAP in C. elegans. Mutants that express only cytosolic forms revealed an essen...

Ubiquitin-dependent control of mitochondrial dynamics is important for protein quality and neuronal integrity. Mitofusins, mitochondrial fusion factors, can integrate cellular stress through their ubiquitylation, which is carried out by multiple E3 enzymes in response to many different stimuli. However, the molecular mechanisms that enable coordina...

The ubiquitin-like proteins Atg8/LC3/GABARAP are required for multiple steps of autophagy, such as initiation, cargo recognition and engulfment, vesicle closure and degradation. Most of LC3/GABARAP functions are considered dependent on their post-translational modifications and their association with the autophagosome membrane through a conjugation...

The ubiquitin-like proteins Atg8/LC3/GABARAP are required for multiple steps of autophagy, such as initiation, cargo recognition and engulfment, vesicle closure and degradation. Most of LC3/GABARAP functions are considered dependent on their post-translational modifications and their association with the autophagosome membrane through a conjugation...

The ubiquitin-like proteins Atg8/LC3/GABARAP are required for multiple steps of autophagy, such as initiation, cargo recognition and engulfment, vesicle closure and degradation. Most of LC3/GABARAP functions are considered dependent on their post-translational modifications and their association with the autophagosome membrane through a conjugation...

The ubiquitin-like proteins Atg8/LC3/GABARAP are required for multiple steps of autophagy, such as initiation, cargo recognition and engulfment, vesicle closure and degradation. Most of LC3/GABARAP functions are considered dependent on their post-translational modifications and their association with the autophagosome membrane through a conjugation...

Muscle is a highly dynamic tissue in which a variety of folding and degradation processes are active to maintain protein homeostasis (proteostasis) and functionality. The muscle-specific chaperone UNC-45 folds the motor protein myosin and assembles it into myofilaments. Malfunction of this chaperone leads to misfolding of myosin, disorganization of...

Mitochondria are central hubs for energy production, metabolism and cellular signal transduction in eukaryotic cells. Maintenance of mitochondrial homeostasis is important for cellular function and survival. In particular, cellular metabolic state is in constant communication with mitochondrial homeostasis. One of the most important metabolic proce...

The endoplasmic reticulum (ER) coordinates mRNA translation and processing of secreted and endomembrane proteins. ER-associated degradation (ERAD) prevents the accumulation of misfolded proteins in the ER, but the physiological regulation of this process remains poorly characterized. Here, in a genetic screen using an ERAD model substrate in Caenor...

Alternations of redox metabolism have been associated with the extension of lifespan in roundworm Caenorhabditis elegans, caused by moderate mitochondrial dysfunction, although the underlying signalling cascades are largely unknown. Previously, we identified transcriptional factor Krüppel-like factor-1 (KLF-1) as the main regulator of cytoprotectiv...

Organismal physiology and survival are influenced by environmental conditions and linked to protein quality control. Proteome integrity is achieved by maintaining an intricate balance between protein folding and degradation. In Caenorhabditis elegans, acute heat stress determines cell non-autonomous regulation of chaperone levels. However, how the...

Branched‐chain amino acid (BCAA) metabolism is a central hub for energy production and regulation of numerous physiological processes. Controversially, both increased and decreased levels of BCAAs are associated with longevity. Using genetics and multi‐omics analyses in Caenorhabditis elegans, we identified adaptive regulation of the ubiquitin‐prot...

The high substrate selectivity of the ubiquitin/proteasome system is mediated by a large group of E3 ubiquitin ligases. The ubiquitin ligase CHIP regulates the degradation of chaperone-controlled and chaperone-independent proteins. To understand how CHIP mediates substrate selection and processing, we performed a structure-function analysis of CHIP...

CHIP (C-terminus of Hsc70-interacting protein) and its worm ortholog CHN-1 are E3 ubiquitin ligases that link the chaperone system with the ubiquitin-proteasome system (UPS). CHN-1 can cooperate with UFD-2, another E3 ligase, to accelerate ubiquitin chain formation; however, the basis for the high processivity of this E3s set has remained obscure....

Temperature is an important environmental condition that determines the physiology and behavior of all organisms. Animals use different response strategies to adapt and survive fluctuations in ambient temperature. The hermaphrodite Caenorhabditis elegans has a well-studied neuronal network consisting of 302 neurons. The bilateral AFD neurons are th...

The conserved Argonaute-family members ALG-1 and ALG-2 are known to regulate processing and maturation of microRNAs to target mRNAs for degradation or translational inhibition (Bouasker and Simard 2012; Meister 2013). Consequently, depletion of alg-1 and alg-2 results in multiple phenotypes. Our data describe a role of microRNA-regulation in stress...

The AAA+ ATPase VCP regulates the extraction of SUMO and ubiquitin-modified DNA replication factors from chromatin. We have previously described that active DNA synthesis is associated with a SUMO-high/ubiquitin-low environment governed by the deubiquitylase USP7. Here, we unveil a functional cooperation between USP7 and VCP in DNA replication, whi...

The E3 ubiquitin ligases CHIP/CHN-1 and UFD-2 team up to accelerate ubiquitin chain formation. However, it remained largely unclear how the high processivity of this E3 set is achieved. Here we studied the molecular mechanism and function of the CHN-1/UFD-2 complex in Caenorhabditis elegans . Our data show that UFD-2 binding promotes the cooperatio...

Cell survival, tissue integrity and organismal health depend on the ability to maintain functional protein networks even under conditions that threaten protein integrity. Protection against such stress conditions involves the adaptation of folding and degradation machineries, which help to preserve the protein network by facilitating the refolding...

The covalent attachment of ubiquitin (Ub) to internal lysine residue(s) of a substrate protein, a process termed ubiquitylation, represents one of the most important posttranslational modifications in eukaryotic organisms. Ubiquitylation is mediated by a sequential cascade of three enzyme classes including ubiquitin-activating enzymes (E1 enzymes),...

A Correction to this paper has been published: https://doi.org/10.1038/s41418-021-00800-4

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...

> link the the full article: https://rdcu.be/cc2Kr < Perturbation of metabolism elicits cellular stress which profoundly modulates the cellular proteome and thus protein homeostasis (proteostasis). Consequently, changes in the cellular proteome due to metabolic shift require adaptive mechanisms by molecular protein quality control. The mechanisms...

the PDF can be download freely on pubmed. https://pubmed.ncbi.nlm.nih.gov/33634751/

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...

The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common...

Sex-specific synaptic connectivity is beginning to emerge as a remarkable, but little explored feature of animal brains. We describe here a novel mechanism that promotes sexually dimorphic neuronal function and synaptic connectivity in the nervous system of the nematode Caenorhabditis elegans. We demonstrate that a phylogenetically conserved, but p...

Sex-specific synaptic connectivity is beginning to emerge as a remarkable, but little explored feature of animal brains. We describe here a novel mechanism that promotes sexually dimorphic neuronal function and synaptic connectivity in the nervous system of the nematode Caenorhabditis elegans. We demonstrate that a phylogenetically conserved, but p...

Sex-specific synaptic connectivity is beginning to emerge as a remarkable, but little explored feature of animal brains. We describe here a novel mechanism that promotes sexually dimorphic neuronal function and synaptic connectivity in the nervous system of the nematode Caenorhabditis elegans. We demonstrate that a phylogenetically conserved, but p...

The BH3-only protein NOXA is a regulator of mitochondrial apoptosis by specifically antagonizing the anti-apoptotic protein MCL-1. Here we show that the E3 ubiquitin ligase CHIP controls NOXA stability after DNA damage. Our findings reveal that CHIP and MCL-1 are binding partners of NOXA and differentially define the fate of NOXA. Whereas NOXA is i...

Sustaining a healthy proteome is a lifelong challenge for each individual cell of an organism. However, protein homeostasis or proteostasis is constantly jeopardized since damaged proteins accumulate under proteotoxic stress that originates from ever-changing metabolic, environmental, and pathological conditions. Proteostasis is achieved via a cons...

Histones modulate gene expression by chromatin compaction, regulating numerous processes such as differentiation. However, the mechanisms underlying histone degradation remain elusive. Human embryonic stem cells (hESCs) have a unique chromatin architecture characterized by low levels of trimethylated histone H3 at lysine 9 (H3K9me3), a heterochroma...

Mitochondria are essential organelles important for energy production, proliferation, and cell death. Biogenesis, homeostasis, and degradation of this organelle are tightly controlled to match cellular needs and counteract chronic stress conditions. Despite providing their own DNA, the vast majority of mitochondrial proteins are encoded in the nucl...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Protein ubiquitylation is essential for the maintenance of cellular homeostasis. E3 ubiquitin ligases are key components of the enzymatic machinery catalyzing the attachment of ubiquitin to substrate proteins. Consequently, enzymatic dysfunction has been associated with medical conditions including cancer, diabetes, and cardiovascular and neurodege...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Autophagy can degrade cargos with the help of selective autophagy receptors such as p62/SQSTM1, which facilitates the degradation of ubiquitinated cargo. While the process of autophagy has been linked to aging, the impact of selective autophagy in lifespan regulation remains unclear. We have recently shown in Caenorhabditis elegans that transcript...

An increasing aging population poses a significant challenge to societies worldwide. A better understanding of the molecular, cellular, organ, tissue, physiological, psychological, and even sociological changes that occur with aging is needed in order to treat age-associated diseases. The field of aging research is rapidly expanding with multiple a...

The pathology of spinocerebellar ataxia type 3, also known as Machado-Joseph disease, is triggered by aggregation of toxic ataxin-3 (ATXN3) variants containing expanded polyglutamine repeats. The physiological role of this deubiquitylase, however, remains largely unclear. Our recent work showed that ATX-3, the nematode orthologue of ATXN3, together...

The maintenance of proteostasis is crucial for any organism to survive and reproduce in an ever-changing environment, but its efficiency declines with age. Post-transcriptional regulators such as microRNAs (miRNAs) control protein translation of target mRNAs, with major consequences for development, physiology and longevity. Here we show that food...

Autophagy is being studied intensively in Caenorhabditis elegans in the context of protein homeostasis and aging. However, in contrast to the yeast and mammalian autophagosomal membrane proteins Atg8 and LC3, lipidation of the C. elegans ortholog LGG-1 with phosphatidylethanolamine has rarely been investigated by western blotting. We attribute this...

Upregulation of Endoplasmic Reticulum-Associated Degradation (ERAD) in the liver upon feeding and organismal growth aggravates proteasomal turnover of the transcription factor CREBH and decreases the expression of its target gene, the hepatokine FGF21. Wei et al and Bhattacharya et al describe the systemic coordination of energy metabolism and orga...

The maintenance of proteostasis is crucial for any organism to survive and reproduce in an ever-changing environment, but its efficiency declines with age. Posttranscriptional regulators such as microRNAs control protein translation of target mRNAs with major consequences for development, physiology, and longevity. However, the precise function of...

Endoplasmic reticulum-associated degradation (ERAD) plays a crucial role in turnover of defective secretory proteins to maintain protein homeostasis. Cha et al. (2018) revealed that the anti-diabetic drug metformin induces ERAD of programmed death ligand (PD-L1), which attenuates tumor growth.

Induced pluripotent stem cells (iPSCs) undergo unlimited self-renewal while maintaining their potential to differentiate into post-mitotic cells with an intact proteome. As such, iPSCs suppress the aggregation of polyQ-expanded huntingtin (HTT), the mutant protein underlying Huntington's disease (HD). Here we show that proteasome activity determine...

Conjugation of ubiquitin onto proteins generates a degradation signal or exerts degradation-independent regulatory functions. Ubiquitylation is governed by the antagonistic action of ubiquitin ligases and deubiquitylating enzymes (DUBs). Several recent publications illustrate a balanced interplay of ligases and DUBs at signaling hubs that are centr...

Labbadia et al. showed that low-dose mitochondrial stress promotes protein homeostasis in the cytosol to endure proteotoxic conditions, particularly during aging. This hormetic mitochondrial stress response is heat shock factor 1 (HSF1)-dependent and, remarkably, does not affect physiological parameters that are usually associated with pathogenic d...

The insulin/insulin‐like growth factor‐1 (IGF‐1) signaling (IIS) pathway is a pivotal genetic program regulating cell growth, tissue development, metabolic physiology, and longevity of multicellular organisms. IIS integrates a fine‐tuned cascade of signaling events induced by insulin/IGF‐1, which is precisely controlled by post‐translational modifi...

The integrity of the cellular proteome is supported by quality control networks, which govern protein synthesis, folding, and degradation. It is generally accepted that an age-related decline in protein homeostasis (proteostasis) contributes to protein aggregation diseases. However, the mechanistic principles underlying proteostasis imbalance and t...

The mammalian ubiquitin ligase Hrd1 is the central component of a complex facilitating degradation of misfolded proteins during the ubiquitin-proteasome dependent process of ER-associated degradation (ERAD). Hrd1 associates with cofactors to execute ERAD, but their roles and how they assemble with Hrd1 are not well understood. Here we identify cruc...

Cellular differentiation, developmental processes, and environmental factors challenge the integrity of the proteome in every eukaryotic cell. The maintenance of protein homeostasis, or proteostasis, involves folding and degradation of damaged proteins, and is essential for cellular function, organismal growth, and viability [1, 2]. Misfolded prote...

Aging is attended by a progressive decline in protein homeostasis (proteostasis), aggravating the risk for protein aggregation diseases. To understand the coordination between proteome imbalance and longevity, we addressed the mechanistic role of the quality-control ubiquitin ligase CHIP, which is a key regulator of proteostasis. We observed that C...

Table S2. chn-1-Deficient Worms Exhibit Delayed Nuclear Localization of DAF-16::GFP Triggered by Heat Shock, Related to Figure 1

Table S1. Statistical Summary of Lifespan Experiments, Related to Figures 1, 5, S1, S2, and S5

Stefan Jentsch reclining in his favorite Le Corbusier chair. Photography by Axel Griesch, with permission from Max Planck Institute of Biochemistry, Martinsried/Munich, Germany. ![][1] With immense sadness, the scientific community along with family and friends mourns the death of Stefan Jentsch, who passed away on October 29, 2016, after a br...

Multiple protein ubiquitination events at DNA double-strand breaks (DSBs) regulate damage recognition, signaling and repair. It has remained poorly understood how the repair process of DSBs is coordinated with the apoptotic response. Here, we identified the E4 ubiquitin ligase UFD-2 as a mediator of DNA-damage-induced apoptosis in a genetic screen...

Selective degradation of proteins requires a fine tuned coordination of the two major proteolytic pathways, the ubiquitin-proteasome system (UPS) and autophagy. Substrate selection and proteolytic activity are defined by a plethora of regulatory cofactors influencing each other. Both proteolytic pathways are initiated by ubiquitylation to mark subs...

Nature Communications 7: Article number: 10612 (2016); Published: 4 February 2016; Updated: 17 May 2016. This Article contains errors in the labelling of Fig. 5 and Supplementary Fig. 6, the former of which was introduced during the production process. In Fig. 5b, an ‘x’ indicating the presence of UBXN-3(SGG)-HIS in lane 6 was inadvertently omitted...

The dynamic composition of proteins associated with nuclear DNA is a fundamental property of chromosome biology. In the chromatin compartment dedicated protein complexes govern the accurate synthesis and repair of the genomic information and define the state of DNA compaction in vital cellular processes such as chromosome segregation or transcripti...

The coordinated activity of DNA replication factors is a highly dynamic process that involves ubiquitin-dependent regulation. In this context, the ubiquitin-directed ATPase CDC-48/p97 recently emerged as a key regulator of chromatin-associated degradation in several of the DNA metabolic pathways that assure genome integrity. However, the spatiotemp...

Supplementary Figures 1-8 and Supplementary Table 1

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring au...

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monit...

In response to DNA damage, cells activate a highly conserved and complex kinase-based signaling network, commonly referred to as the DNA damage response (DDR), to safeguard genomic integrity. The DDR consists of a set of tightly regulated events, including detection of DNA damage, accumulation of DNA repair factors at the site of damage, and finall...

The maintenance of protein homeostasis (proteostasis) is key in preserving the healthy state of single cells and life expectancy of entire organisms. To ensure proteome integrity, stress responsive pathways are induced to counteract aggregate formation by boosting the cellular protein folding capacity. In addition, irreversibly damaged proteins are...

The endoplasmic reticulum (ER) is a cellular compartment that has a key function in protein translation and folding. Maintaining its integrity is of fundamental importance for organism's physiology and viability. The dynamic regulation of intraluminal ER Ca(2+) concentration directly influences the activity of ER-resident chaperones and stress resp...

The maintenance of protein homeostasis (proteostasis) is key in preserving the healthy state of single cells and life expectancy of entire organisms. To ensure proteome integrity, stress responsive pathways are induced to counteract aggregate formation by boosting the cellular protein folding capacity. In addition, irreversibly damaged proteins are...

Proteome stability is central to cellular function and the lifespan of an organism. This is apparent in muscle cells, where incorrect folding and assembly of the sarcomere contributes to disease and aging. Apart from the myosin-assembly factor UNC-45, the complete network of chaperones involved in assembly and maintenance of muscle tissue is curren...

Cdc48/p97 is an evolutionary conserved ubiquitin-dependent chaperone involved in a broad array of cellular functions due to its ability to associate with multiple cofactors. Aside from its role in removing RNA polymerase II from chromatin after DNA damage, little is known about how this AAA-ATPase is involved in the transcriptional process. Here, w...

The 26S proteasome is a protease complex that completely degrades substrate proteins marked with a chain of ubiquitins, but is also able to perform endoproteolytic cleavage. A new study now demonstrates that regulated ubiquitin-proteasome-dependent processing ameliorates proteasomal inhibition.

In eukaryotic cells, proteasomes exist primarily as 26S holoenzymes, the most efficient configuration for ubiquitinated protein degradation. Here, we show that acute oxidative stress caused by environmental insults or mitochondrial defects results in rapid disassembly of 26S proteasomes into intact 20S core and 19S regulatory particles. Consequentl...

Significance The unfolded protein response of the endoplasmic reticulum (UPR ER ) is induced by proteotoxic conditions. Lipid disequilibrium also activates the UPR ER , but whether this activation is accompanied by disturbed proteostasis in vivo remains controversial. In this study, we show that in the nematode Caenorhabditis elegans compromised fa...

Protein homeostasis is essential for cellular function, organismal growth and viability. Damaged and aggregated proteins are turned over by two major proteolytic routes of the cellular quality-control pathways: the ubiquitin-proteasome system and autophagy. For both these pathways, ubiquitination provides the recognition signal for substrate select...

Mitochondria maintain cellular homeostasis by coordinating ATP synthesis with metabolic activity, redox signaling, and apoptosis. Excessive levels of mitochondria-derived reactive oxygen species (ROS) promote mitochondrial dysfunction, triggering numerous metabolic disorders. However, the molecular basis for the harmful effects of excessive ROS for...

Aging entails a progressive decline in protein homeostasis, which often leads to age-related diseases. The endoplasmic reticulum (ER) is the site of protein synthesis and maturation for secreted and membrane proteins. Correct folding of ER proteins requires covalent attachment of N-linked glycan oligosaccharides. Here, we report that increased synt...

Sirtuins, a family of histone deacetylases, have a fiercely debated role in regulating lifespan. In contrast with recent observations, here we find that overexpression of sir-2.1, the ortholog of mammalian SirT1, does extend Caenorhabditis elegans lifespan. Sirtuins mandatorily convert NAD(+) into nicotinamide (NAM). We here find that NAM and its m...

DNA damage responses have been well characterized with regard to their cell-autonomous checkpoint functions leading to cell cycle arrest, senescence and apoptosis. In contrast, systemic responses to tissue-specific genome instability remain poorly understood. In adult Caenorhabditis elegans worms germ cells undergo mitotic and meiotic cell division...