Alexandra Stolz

Goethe-Universität Frankfurt am Main · Buchmann Institute for Molecular Life Sciences (BMLS)

The Endoplasmic Reticulum (ER) is the largest cellular organelle that undergoes constant turnover upon diverse functional demands and cellular signals. Removal of non-functional or superfluous subdomains is balanced by the parallel expansion and formation of ER membranes leading to the dynamic exchange of ER components. In recent years, selective a...

Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, an...

Autophagy activation has the potential to ameliorate neurodegenerative disease phenotypes, including protein aggregation, lipid level perturbations and axonal trafficking defects. We performed a high content imaging-based screen assessing 940,000 small molecules to identify those that accelerate lipid droplet clearance. Hits were validated in diver...

Selective autophagy is a quality control pathway through which cellular components are sequestered into double-membrane vesicles and delivered to specific intracellular compartments. This process requires autophagy receptors that link cargo to growing autophagosomal membranes. Selective autophagy is also implicated in various membrane trafficking e...

Autophagy is a cellular process implicated in the renewal of cellular components and the maintenance of cellular hemostasis and therefore associated with various types of diseases. In addition, autophagy belongs to the stress response pathways and is frequently activated by chemical compounds harboring characteristics of cell toxicity. High-through...

Selective autophagy of the ER (ERphagy) is an important regulator of ER remodeling and critical to maintain cellular homeostasis upon environmental changes. ERphagy receptors link the ER with autophagic membrane thus regulating ERphagy flux. We recently showed that members of the FAM134 family play overlapping and distinct roles during stress-induc...

Hereditary sensory and autonomic neuropathy 9 (HSAN9) is a rare fatal neurological disease caused by mis- and nonsense mutations in the gene encoding for Tectonin β-propeller repeat containing protein 2 (TECPR2). While TECPR2 is required for lysosomal consumption of autophagosomes and ER-to-Golgi transport, it remains elusive how exactly TECPR2 is...

Selective degradation of the endoplasmic reticulum (ER) via autophagy (ER-phagy) is initiated by ER-phagy receptors, which facilitate the incorporation of ER fragments into autophagosomes. FAM134 reticulon family proteins (FAM134A, FAM134B, and FAM134C) are ER-phagy receptors with structural similarities and nonredundant functions. Whether they res...

Calcium (Ca2+) elevation is an essential secondary messenger in many cellular processes, including disease progression and adaptation to external stimuli, e.g., gravitational load. Therefore, mapping and quantifying Ca2+ signaling with a high spatiotemporal resolution is a key challenge. However, particularly on microgravity platforms, experiment t...

Autophagy is a major cellular quality control system responsible for degradation of proteins and organelles in response to stress and damage in order to maintain homeostasis. Ubiquitination of autophagy-related proteins or regulatory components is important for the precise control of autophagy pathways. Here, we show that the deubiquitinase USP11 r...

Autophagy is a core molecular pathway for the preservation of cellular and organismal homeostasis. Pharmacological and genetic interventions impairing autophagy responses promote or aggravate disease in a plethora of experimental models. Consistently, mutations in autophagy-related processes cause severe human pathologies. Here, we review and discu...

Degradation of the endoplasmic reticulum (ER) via selective autop-hagy (ER-phagy) is vital for cellular homeostasis. We identify FAM134A/RETREG2 and FAM134C/RETREG3 as ER-phagy receptors, which predominantly exist in an inactive state under basal conditions. Upon autophagy induction and ER stress signal, they can induce significant ER fragmentation...

We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inh...

Selective degradation of the endoplasmic reticulum (ER; reticulophagy) is a type of autophagy involved in the removal of ER fragments. So far, amino acid starvation as well as ER stress have been described as inducers of reticulophagy, which in turn restores cellular energy levels and ER homeostasis. Here, we explored the autophagy-inducing mechani...

The family of bacterial SidE enzymes catalyzes non-canonical phosphoribosyl-linked (PR) serine ubiquitination and promotes infectivity of Legionella pneumophila. Here, we describe identification of two bacterial effectors that reverse PR ubiquitination and are thus named deubiquitinases for PR ubiquitination (DUPs; DupA and DupB). Structural analys...

We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inh...

The endoplasmic reticulum (ER) is a large and dynamic cellular organelle. ER morphology consists of sheets, tubules, matrixes and contact sites shared with other membranous organelles. The capacity of the ER to fulfil its numerous biological functions depends on its continuous remodeling and the quality control of its proteome. Selective turnover o...

Autophagy is essential for cellular homeostasis and when deregulated this survival mechanism has been associated with disease development. Inhibition of autophagy initiation by inhibiting the kinase ULK1 (Unc-51-like autophagy activating kinase 1) has been proposed as a potential cancer therapy. While inhibitors and crystal structures of ULK1 have...

Autophagy is essential for cellular homeostasis and when deregulated this survival mechanism has been associated with disease development. Inhibition of autophagy initiation by inhibiting the kinase ULK1 has been proposed as a potential cancer therapy. While inhibitors and crystal structures of ULK1 have been reported, little is known about the oth...

hrough the canonical LC3 interaction motif (LIR), [W/F/Y]‐X1‐X2‐[I/L/V], protein complexes are recruited to autophagosomes to perform their functions as either autophagy adaptors or receptors. How these adaptors/receptors selectively interact with either LC3 or GABARAP families remains unclear. Herein, we determine the range of selectivity of 30 kn...

Selective autophagy represents the major quality control mechanism that ensures proper turnover of exhausted or harmful organelles, among them the endoplasmic reticulum (ER), which is fragmented and delivered to the lysosome for degradation via a specific type of autophagy called ER-phagy. The recent discovery of ER-resident proteins that bind to m...

PINK1 and parkin proteins help to degrade damaged mitochondrial organelles, and abnormalities in these proteins are linked to Parkinson’s disease. Mouse studies reveal that the proteins act to prevent inflammation. PINK1 and parkin proteins prevent inflammation caused by mitochondria.

The biological diversity of ubiquitination resides in the multivalent nature of linkage-specific homotypic and heterotypic ubiquitin (Ub) chains. A recent publication by Yau et al. in Cell describes the development of K11/K48-bispecific antibodies and a physiological role for K11/K48 heterotypic chains in regulation of the cell cycle and clearance...

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Through the canonical LC3 interaction motif (LIR), [W/F/Y]-X1-X2-[I/ L/V], protein complexes are recruited to autophagosomes to perform their functions as either autophagy adaptors or receptors. How these adaptors/receptors selectively interact with either LC3 or GABARAP families remains unclear. Herein, we determine the range of selectivity of 30...

Autophagy is a cellular surveillance pathway that balances metabolic and energy resources and transports specific cargos, including damaged mitochondria, other broken organelles, or pathogens for degradation to the lysosome. Central components of autophagosomal biogenesis are six members of the LC3 and GABARAP family of ubiquitin-like proteins (mAT...

Through the canonical LC3 interaction motif (LIR), [W/F/Y]-X 1 -X 2 -[I/L/V], protein complexes are recruited to autophagosomes to perform their functions as either autophagy adaptors or receptors. How these adaptors/receptors selectively interact with either LC3 or GABARAP families remains unclear. Herein, we determine the range of selectivity of...

Significance Selective autophagy of damaged mitochondria (mitophagy) requires protein kinases PINK1 and TBK1, ubiquitin ligase Parkin, and autophagy receptors such as OPTN, driving ubiquitin-labeled mitochondria into autophagosomes. Because all proteins have been genetically linked to either Parkinson’s disease (PINK1 and Parkin) or amyotrophic lat...

The endoplasmic reticulum (ER) is the largest intracellular endomembrane system, enabling protein and lipid synthesis, ion homeostasis, quality control of newly synthesized proteins and organelle communication. Constant ER turnover and modulation is needed to meet different cellular requirements and autophagy has an important role in this process....

By using quantitative proteomics, Ordureau et al. (2014) provide a comprehensive view on the regulatory steps by which PINK1-mediated phosphorylation of PARKIN and ubiquitin triggers the recruitment of the ubiquitin ligase PARKIN to damaged mitochondria. Copyright © 2014 Elsevier Inc. All rights reserved.

Significance The study describes a previously unknown role for the cytosolic ubiquitin ligase Ubr1 in endoplasmic reticulum-associated protein degradation, thereby connecting the protein quality control processes of the endoplasmic reticulum and of the cytosol.

Mutated derivatives of carboxypeptidase yscY (CPY) are potent substrates to study protein quality control and protein degradation in different cell compartments in yeast. Depending on the subcellular compartment of interest, the design of the model substrate used has to be adapted. Here, we describe the derivatives of CPY*used in genetic screens ba...

Proteins, featured with a multitude of enzymatic activities as well as structural and other physiological functions are the main operators in the cell. Proteins are synthesized in the cytosol by ribosomes, which use m-RNA as a template to translate DNA based structural information into an amino acid sequence. During translation many errors occur re...

In eukaryotes, membrane and soluble proteins of the secretory pathway enter the endoplasmic reticulum (ER) after synthesis in an unfolded state. Directly after entry, most proteins are modified with glycans at suitable glycosylation sites and start to fold. A protein that cannot fold properly will be degraded in a process called ER associated degra...

The AAA-type ATPase Cdc48 (named p97/VCP in mammals) is a molecular machine in all eukaryotic cells that transforms ATP hydrolysis into mechanic power to unfold and pull proteins against physical forces, which make up a protein's structure and hold it in place. From the many cellular processes, Cdc48 is involved in, its function in endoplasmic reti...

The endoplasmic reticulum (ER) is responsible for folding and delivery of secretory proteins to their site of action. One major modification proteins undergo in this organelle is N-glycosylation. Proteins that cannot fold properly will be directed to a process known as endoplasmic reticulum associated degradation (ERAD). Processing of N-glycans gen...

Cdc48 is an essential, highly prominent ATP driven machine in eukaryotic cells. Physiological function of Cdc48 has been found in a multitude of cellular processes, for instance cell cycle progression, homotypic membrane fusion, chromatin remodeling, transcriptional and metabolic regulation, and many others. The molecular function of Cdc48 is argua...

Proteins imported into the endoplasmic reticulum (ER) are scanned for their folding status. Those that do not reach their native conformation are degraded via the ubiquitin-proteasome system. This process is called ER-associated degradation (ERAD). Der1 is known to be one of the components required for efficient degradation of soluble ERAD substrat...

Recognition and elimination of misfolded proteins are essential cellular processes. More than thirty percent of the cellular proteins are proteins of the secretory pathway. They fold in the lumen or membrane of the endoplasmic reticulum from where they are sorted to their site of action. The folding process, as well as any refolding after cell stre...