Immune Signaling
The research of the Immune Signaling group aims to decipher how signaling cascades, influenced by post-translational modifications, govern cellular homeostasis and react to invading pathogens (bacteria and viruses).
Dr. Lina Herhaus
After high school, Lina obtained her first lab work experience in Mexico at the Research center ECOSUR. She then decided to study Applied Biology at the Hochschule Bonn-Rhein-Sieg (Germany) and Molecular Biology at the University of Dundee (UK). She obtained a double degree with Honors. Lina performed her Ph.D. studies at the MRC Protein Phosphorylation and Ubiquitylation Unit in Dundee under Gopal Sapkota. Her dissertation focused on deubiquitylating enzymes regulating the TGF-beta and BMP signaling pathways. Following her Ph.D. studies, Lina received an EMBO fellowship for her postdoctoral research in the lab of Ivan Dikic to work on linear ubiquitylation and autophagy. After her postdoctoral work, she joined the Frankfurt Cancer Institute as a cellular and biochemical analysis platform staff scientist. Lina is now a team leader of the Immune Signaling program, which aims to decipher TBK1-mediated signaling in different pathologies.
Dr. Aparna Viswanathan Ammanath
Aparna is originally from Kerala, India. She obtained her PhD from Dept. of Microbial Genetics, Institute of Medical Microbiology and Hygiene, University of Tübingen. Her work focused on development of narrow spectrum anti-infective peptides from Staphylococcus aureus lipoprotein. Previously, she worked at the Center for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, India, developing polymer based gels and nanoparticles for wound healing in mice models.
Uxía Gestal Mato
Uxía was born in A Coruña, Spain. In 2018, she obtained her bachelor’s degree in Biotechnology from Universidad Francisco de Vitoria (Madrid), together with an accompanying degree as “Expert in biotechnological research methodology”. For her BSc thesis, she joined Prof. Ivan Dikic’s group where she focused on the regulation of selective autophagy pathways and their contribution to host defense against intracellular pathogens. Later, she enrolled in the MSc Program of Molecular Biosciences at Heidelberg University, where she majored in Molecular and Cellular Biology. During her stay in Heidelberg, she had the opportunity to discover different fields of research as a rotation student in the groups of Prof. Melchior, Prof. Schuck, and Prof. Krause. She has now joined the Herhaus Group as a master student to study autophagy and its role in immune signaling.
Past Members:
Ivan Bagaric
Ivan has joined the laboratory for his bachelor thesis to study autophagy in the context of immune signaling. Supervised by Lina Herhaus, he focused on the interaction of the Immunity related GTPase Q (IRGQ) with the autophagy machinery and its impact on immune signaling using biochemical assays and fluorescence microscopy. He is currently enrolled in the Master's program "Molecular Biosciences" at the University of Heidelberg majoring in Molecular and Cellular Biology.
Jeannett Smidt-Larsen
Is originally from Denmark and is doing a bachelor's in Laboratory Technician in Denmark at the business academy Aarhus. She joined the Ivan Dikic lab in August 2020 for a year internship as a part of her Education.
Herhaus L, Gestal-Mato U, Eapen VV, Mačinković I, Bailey HJ, Prieto-Garcia C, Misra M, Jacomin AC, Ammanath AV, Bagarić I, Michaelis J, Vollrath J, Bhaskara RM, Bündgen G, Covarrubias-Pinto A, Husnjak K, Zöller J, Gikandi A, Ribičić S, Bopp T, van der Heden van Noort GJ, Langer JD, Weigert A, Harper JW, Mancias JD, et al. IRGQ-mediated autophagy in MHC class I quality control promotes tumor immune evasion. Cell 2024. 187 (25) 7285-7302.e29 Link
Krämer N, Mato UG, Krauter S, Büscher N, Afifi A, Herhaus L, Florin L, Plachter B, Zimmermann C The Autophagy Receptor /p62 Is a Restriction Factor of HCMV Infection. Viruses 2024. 16 (9) Link
Weigert A, Herhaus L Immune modulation through secretory autophagy. J Cell Biochem 2024. 125 (11) e30427 Link
Gestal-Mato U, Herhaus L Autophagy-dependent regulation of MHC-I molecule presentation. J Cell Biochem 2024. 125 (11) e30416 Link
Krämer N, Schütz M, Mato UG, Herhaus L, Marschall M, Zimmermann C Recombinant Human Cytomegalovirus Expressing an Analog-Sensitive Kinase pUL97 as Novel Tool for Functional Analyses. Viruses 2022. 14 (10) Link
Hahn M, Covarrubias-Pinto A, Herhaus L, Satpathy S, Klann K, Boyle KB, Münch C, Rajalingam K, Randow F, Choudhary C, Dikic I SIK2 orchestrates actin-dependent host response upon infection. Proc Natl Acad Sci U S A 2021. 118 (19) Link
Herhaus L TBK1 (TANK-binding kinase 1)-mediated regulation of autophagy in health and disease. Matrix Biol 2021. 100-101 84-98 Link
Herhaus L, Bhaskara RM, Lystad AH, Gestal-Mato U, Covarrubias-Pinto A, Bonn F, Simonsen A, Hummer G, Dikic I TBK1-mediated phosphorylation of LC3C and GABARAP-L2 controls autophagosome shedding by ATG4 protease. EMBO Rep 2020. 21 (1) e48317 Link
Herhaus L, van den Bedem H, Tang S, Maslennikov I, Wakatsuki S, Dikic I, Rahighi S Molecular Recognition of M1-Linked Ubiquitin Chains by Native and Phosphorylated UBAN Domains. J Mol Biol 2019. 431 (17) 3146-3156 Link
Herhaus L, Dikic I Dimerization quality control via ubiquitylation. Science 2018. 362 (6411) 151-152 Link
Herhaus L, Dikic I Ubiquitin-induced phase separation of p62/SQSTM1. Cell Res 2018. 28 (4) 389-390 Link
Herhaus L, Dikic I Regulation of Salmonella-host cell interactions via the ubiquitin system. Int J Med Microbiol 2018. 308 (1) 176-184 Link
van Wijk SJL, Fricke F, Herhaus L, Gupta J, Hötte K, Pampaloni F, Grumati P, Kaulich M, Sou YS, Komatsu M, Greten FR, Fulda S, Heilemann M, Dikic I Linear ubiquitination of cytosolic Salmonella Typhimurium activates NF-κB and restricts bacterial proliferation. Nat Microbiol 2017. 2 17066 Link
Fiskin E, Bhogaraju S, Herhaus L, Kalayil S, Hahn M, Dikic I Structural basis for the recognition and degradation of host TRIM proteins by Salmonella effector SopA. Nat Commun 2017. 8 14004 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
Herhaus L, Dikic I Expanding the ubiquitin code through post-translational modification. EMBO Rep 2015. 16 (9) 1071-83 Link
Rojas-Fernandez A, Herhaus L, Macartney T, Lachaud C, Hay RT, Sapkota GP Rapid generation of endogenously driven transcriptional reporters in cells through CRISPR/Cas9. Sci Rep 2015. 5 9811 Link
Herhaus L, Perez-Oliva AB, Cozza G, Gourlay R, Weidlich S, Campbell DG, Pinna LA, Sapkota GP Casein kinase 2 (CK2) phosphorylates the deubiquitylase OTUB1 at Ser16 to trigger its nuclear localization. Sci Signal 2015. 8 (372) ra35 Link
Tan L, Nomanbhoy T, Gurbani D, Patricelli M, Hunter J, Geng J, Herhaus L, Zhang J, Pauls E, Ham Y, Choi HG, Xie T, Deng X, Buhrlage SJ, Sim T, Cohen P, Sapkota G, Westover KD, Gray NS Discovery of type II inhibitors of TGFβ-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2). J Med Chem 2015. 58 (1) 183-96 Link
Herhaus L, Sapkota GP The emerging roles of deubiquitylating enzymes (DUBs) in the TGFβ and BMP pathways. Cell Signal 2014. 26 (10) 2186-92 Link
Herhaus L, Al-Salihi MA, Dingwell KS, Cummins TD, Wasmus L, Vogt J, Ewan R, Bruce D, Macartney T, Weidlich S, Smith JC, Sapkota GP USP15 targets ALK3/BMPR1A for deubiquitylation to enhance bone morphogenetic protein signalling. Open Biol 2014. 4 (5) 140065 Link
Vogt J, Dingwell KS, Herhaus L, Gourlay R, Macartney T, Campbell D, Smith JC, Sapkota GP Protein associated with SMAD1 (PAWS1/FAM83G) is a substrate for type I bone morphogenetic protein receptors and modulates bone morphogenetic protein signalling. Open Biol 2014. 4 (2) 130210 Link
Herhaus L, Al-Salihi M, Macartney T, Weidlich S, Sapkota GP OTUB1 enhances TGFβ signalling by inhibiting the ubiquitylation and degradation of active SMAD2/3. Nat Commun 2013. 4 2519 Link
Al-Salihi MA, Herhaus L, Macartney T, Sapkota GP USP11 augments TGFβ signalling by deubiquitylating ALK5. Open Biol 2012. 2 (6) 120063 Link
Al-Salihi MA, Herhaus L, Sapkota GP Regulation of the transforming growth factor β pathway by reversible ubiquitylation. Open Biol 2012. 2 (5) 120082 Link
TANK-binding kinase 1 (TBK1) is a multifunctional serine/threonine protein kinase that belongs to the noncanonical IkB kinase family and exerts a broad spectrum of functions in cells, ranging from anti-viral immunity, inflammation and IFN signaling, through selective autophagy, specifically mitophagy and xenophagy, to EMT and energy homeostasis. Thus, it is not surprising that TBK1 is involved in many cellular signaling pathways that contribute to oncogenesis or neurological diseases.
TBK1 links inflammatory pathways to autophagy, which is a quality control process to deliver cytosolic components for targeted lysosomal degradation. It promotes protein/organelle homeostasis during selective autophagy by phosphorylating autophagy modifiers and receptors, thereby regulating autophagy during various steps of autophagosome formation (Herhaus et al., 2015; Richter et al.,2016; Herhaus et al., 2019). Moreover, TBK1 plays a central role in innate immunity, as it acts as an integrator of receptor-mediated pathogen detection signals and IFN level modulator. In conclusion, TBK1 is a central kinase at the crossroads of inflammatory interferon signaling and selective autophagy.
How these highly orchestrated TBK1 signaling cascades interact and contribute to human diseases is not well understood. In our lab, we aim to evaluate different TBK1-mediated pathways, by employing state-of-the-art mass spectrometry and imaging facilities, together with classical biochemical assays. This research will provide us with a mechanism-based rationale for the development of new therapeutics.
Institute of Biochemistry II
University Hospital Frankfurt
Goethe University
Theodor-Stern-Kai 7 / Building 75
60590 Frankfurt am Main
Germany
Tel: +49 (0) 69 6301 83816
Herhaus@em.uni-frankfurt.de
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