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 fulfill its numerous biological functions depends on its continuous remodeling and the quality control of its proteome. Selective turnover of the ER membrane and ER proteins by autophagy and the proteasome, termed ER-phagy and ER associated protein degradation (ERAD) respectively, play important roles in maintaining ER morphology and functions. Research in the Stolz group focuses on different aspects of ER quality control and the crosstalk between different stress resolving pathways.
We are grateful to the funders of our work: CRC 1177 on Selective Autophagy (SFB); IMI EUbOPEN / IMI 875510 / Horizon 2020; DFG WO 210/20-2; Goethe University Frankfurt
Alexandra Stolz studied Biochemistry in Regensburg, Germany followed by a PhD in yeast genetics and molecular biology in Stuttgart, Germany. After a postdoc (2012-2013) working on ER associated protein degradation (ERAD) – a proteasome dependent pathway, Alexandra joined the groups of Andreas Ernst and Ivan Dikic at IBC2 in Frankfurt, Germany (2013-2016) to work on autophagy. Besides contributing to the characterization of the first autophagy receptor for ER-phagy FAM134B and elaborating the role of the kinase TBK1 in mitophagy, she utilized phage display and protein engineering to develop fluorescent sensors for the central autophagy components LC3/GABARAPs. In January 2017, she joined Genentech in South San Francisco, USA as a visiting scientist where she studied the impact of oncogene-induced secretion during cancer pathogenesis. Since February 2018, Alexandra is the team leader of the ER quality control group located at the Buchman Institute for Molecular Life Sciences (BMLS). Alexandra is also associated with the SGC Frankfurt, where her group aims to target different components of the autophagic machinery including kinases, autophagy receptors and individual LC3/GABARAPs to block or enhance specific canonical and non-canonical autophagy pathways.
Rayene is originally from Constantine, Algeria. She obtained her first Mater’s degree in human genetics with honor from the University Constantine. In Sep. 2017, she moved to France where she obtained a second Masters in Cancer Biology from Montpellier University. In Feb. 2020, Rayene moved to Frankfurt and joined the Stolz group as a Master’s intern. In her project, she focused mainly on the establishment of drug screening assays in lung cancer cell lines cultured in 2D and 3D, respectively. After completing her Master’s thesis, Rayene intended to explore another horizon and proceeded as a PhD student, shifting her focus towards deciphering the molecular mechanism of ER quality control check mechanism around the FAM134 family.
Sara is studying Biotechnology at the University Francisco de Vitoria, Spain and joined the lab in September 2020 for her Bachelor thesis. In her research Sara analysis the impact of kinase signaling in 2D vs. 3D cultured cells.
In July 2016 Wenbo obtained his master degree in Institute of Biophysics, Chinese Academy of Sciences, where he received preliminary training in the field of cryo-electron microscopy(cryo-EM). Afterwards Wenbo initiated his PhD study in Max-Planck-Institute of Biophysics and researched the structures of rabbit ryanodine receptor 1 (RyR1) in native membrane by cryo-EM, he will finish his PhD study in August 2020 and join the Dikic lab and Stolz group as postdoc researcher since September 2020. Wenbo will on one side carry out structural studies of important proteins involved in autophagy and ubiquitylation by cryo-EM in Dikic lab, on another side he will also start to work in a new field, which is the ER quality control group led by Dr. Alexandra Stolz.
Gina joined the lab in 2018 on a collaborative project with the Knapp group, focusing on the development and analysis of inhibitors targeting kinases of the CLK and SRPK family.
After studying Biology at the Belgrad University, Serbia, Katarina finished her bachelor degree in molecular biology and subsequent master degree in biomedicine at the Johannes Gutenberg University Mainz, Germany. In 2018 Katarina joined the group for 7 months on a qualification scholarship working on the establishment cell based autophagy assays before moving on to an industrial position.
Pablo joined the group in 2018, during his last year of his biotechnology degree at Universidad Francisco de Vitoria (Madrid), to develop his bachelor thesis and lab experience. He stayed for 7 months working on the establishment of cell-based autophagy assays as well as the characterization of different interactors of autophagy receptors. Pablo later enrolled in the Master of Neuroscience of the Autonoma University of Madrid and made his Master thesis at the Spanish National Cancer Research Center (CNIO).
Sandra joined the lab in 2020 for her bachelor thesis, focusing on the impact of selected small molecules on general autophagy and ER-phagy flux, respectively.
Wells CI, Al-Ali H, Andrews DM, Asquith CRM, Axtman AD, Dikic I, Ebner D, Ettmayer P, Fischer C, Frederiksen M, Futrell RE, Gray NS, Hatch SB, Knapp S, Lücking U, Michaelides M, Mills CE, Müller S, Owen D, Picado A, Saikatendu KS, Schröder M, Stolz A, Tellechea M, Turunen BJ, et al. The Kinase Chemogenomic Set (KCGS): An Open Science Resource for Kinase Vulnerability Identification. Int J Mol Sci 2021. 22 (2) Link
Zielke S, Kardo S, Zein L, Mari M, Covarrubias-Pinto A, Kinzler MN, Meyer N, Stolz A, Fulda S, Reggiori F, Kögel D, van Wijk S ATF4 links ER stress with reticulophagy in glioblastoma cells. Autophagy 2020. 1-17 Link
Shin D, Mukherjee R, Liu Y, Gonzalez A, Bonn F, Liu Y, Rogov VV, Heinz M, Stolz A, Hummer G, Dötsch V, Luo ZQ, Bhogaraju S, Dikic I Regulation of Phosphoribosyl-Linked Serine Ubiquitination by Deubiquitinases DupA and DupB. Mol Cell 2020. 77 (1) 164-179.e6 Link
Stolz A, Grumati P The various shades of ER-phagy. FEBS J 2019. 286 (23) 4642-4649 Link
Chaikuad A, Koschade SE, Stolz A, Zivkovic K, Pohl C, Shaid S, Ren H, Lambert LJ, Cosford NDP, Brandts CH, Knapp S Conservation of structure, function and inhibitor binding in UNC-51-like kinase 1 and 2 (ULK1/2). Biochem J 2019. 476 (5) 875-887 Link
Rogov VV, Stolz A, Ravichandran AC, Rios-Szwed DO, Suzuki H, Kniss A, Löhr F, Wakatsuki S, Dötsch V, Dikic I, Dobson RC, McEwan DG Structural and functional analysis of the GABARAP interaction motif (GIM). EMBO Rep 2018. 19 (12) Link
Stolz A, Dikic I Elusive mitochondrial connection to inflammation uncovered. Nature 2018. 561 (7722) 185-186 Link
Grumati P, Dikic I, Stolz A ER-phagy at a glance. J Cell Sci 2018. 131 (17) Link
Stolz A, Dikic I Heterotypic Ubiquitin Chains: Seeing is Believing. Trends Cell Biol 2018. 28 (1) 1-3 Link
Rogov VV, Stolz A, Ravichandran AC, Rios-Szwed DO, Suzuki H, Kniss A, Löhr F, Wakatsuki S, Dötsch V, Dikic I, Dobson RC, McEwan DG Structural and functional analysis of the GABARAP interaction motif (GIM). EMBO Rep 2017. 18 (8) 1382-1396 Link
Stolz A, Putyrski M, Kutle I, Huber J, Wang C, Major V, Sidhu SS, Youle RJ, Rogov VV, Dötsch V, Ernst A, Dikic I Fluorescence-based ATG8 sensors monitor localization and function of LC3/GABARAP proteins. EMBO J 2017. 36 (4) 549-564 Link
Richter B, Sliter DA, Herhaus L, Stolz A, Wang C, Beli P, Zaffagnini G, Wild P, Martens S, Wagner SA, Youle RJ, Dikic I Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proc Natl Acad Sci U S A 2016. 113 (15) 4039-44 Link
Khaminets A, Heinrich T, Mari M, Grumati P, Huebner AK, Akutsu M, Liebmann L, Stolz A, Nietzsche S, Koch N, Mauthe M, Katona I, Qualmann B, Weis J, Reggiori F, Kurth I, Hübner CA, Dikic I Regulation of endoplasmic reticulum turnover by selective autophagy. Nature 2015. 522 (7556) 354-8 Link
Stolz A, Dikic I PINK1-PARKIN interplay: down to ubiquitin phosphorylation. Mol Cell 2014. 56 (3) 341-2 Link
Stolz A, Ernst A, Dikic I Cargo recognition and trafficking in selective autophagy. Nat Cell Biol 2014. 16 (6) 495-501 Link
Stolz A, Besser S, Hottmann H, Wolf DH Previously unknown role for the ubiquitin ligase Ubr1 in endoplasmic reticulum-associated protein degradation. Proc Natl Acad Sci U S A 2013. 110 (38) 15271-6 Link
Stolz A, Wolf DH Use of CPY and its derivatives to study protein quality control in various cell compartments. Methods Mol Biol 2012. 832 489-504 Link
Martinez Benitez E, Stolz A, Becher A, Wolf DH Mnl2, a novel component of the ER associated protein degradation pathway. Biochem Biophys Res Commun 2011. 414 (3) 528-32 Link
Wolf DH, Stolz A The Cdc48 machine in endoplasmic reticulum associated protein degradation. Biochim Biophys Acta 2012. 1823 (1) 117-24 Link
Benitez EM, Stolz A, Wolf DH Yos9, a control protein for misfolded glycosylated and non-glycosylated proteins in ERAD. FEBS Lett 2011. 585 (19) 3015-9 Link
Stolz A, Hilt W, Buchberger A, Wolf DH Cdc48: a power machine in protein degradation. Trends Biochem Sci 2011. 36 (10) 515-23 Link
Stolz A, Schweizer RS, Schäfer A, Wolf DH Dfm1 forms distinct complexes with Cdc48 and the ER ubiquitin ligases and is required for ERAD. Traffic 2010. 11 (10) 1363-9 Link
Stolz A, Wolf DH Endoplasmic reticulum associated protein degradation: a chaperone assisted journey to hell. Biochim Biophys Acta 2010. 1803 (6) 694-705 Link
ER network integrity and turnover by autophagy rely on specific ER-phagy receptors, which influence and coordinate alterations in ER morphology and the degradation of ER contents and membranes via the lysosome, by interacting with the LC3/GABARAP family. The first mammalian ER-phagy receptor, FAM134B, was identified in our institute. My laboratory is specifically interested in its two family members - FAM134A and FAM134C – in potential overlapping and distinct functions as well as their crosstalk and regulation.
The ERAD process is organized around ER resident, membrane-embedded E3 ubiquitin ligases forming distinct protein complexes and collectively providing the essential substrate ubiquitination activity for degradation of ERAD substrates by the proteasome. Recent high-resolution structures revealed that the yeast E3 ligase Hrd1 and the rhomboid pseudoprotease Der1 provide a sizable pore for the dislocation of luminal proteins into the cytoplasm. In collaboration with Marius Lemberg and Dönem Avci (Uni Heidelberg), we aim to define the precise physiological role of Dfm1 in S. cerevisae, identify endogenous substrates, and decipher the molecular mechanism of membrane protein degradation in the ER – potentially linking ERAD and ER-phagy
We utilize microscopy instruments (Sartorius IncuCyte S3 and Yokogawa CQ1) to perform cell-based assays. Depending on the scientific question, we use a variety of fluorescent labeled reporter cell lines and compound libraries to identify signaling pathways or study the impact of specific stress and pathway alterations on cell proliferation. To allow semi-high throughput our assays are mostly performed in 384-well plate format, including triplicates of each tested condition as well as standard control compounds on each plate for comparison and quality control. We are able to precisely handle minimal amount of compounds with the help of Labcyte’s ECHO 555 liquid handler.
Part of our efforts is channeled into the establishment of spheroid based 3D assays. Their remarkable clinical relevance and realistic setting in respect of cellular behavior and pharmacological response compared to 2D cell culture make them powerful tools for biologic studies and drug development.