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).
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) where she obtained a double degree with Honors. Lina performed her PhD studies at the MRC Protein Phosphorylation and Ubiquitylation Unit in Dundee under the supervision of Gopal Sapkota. Her dissertation focused on how deubiquitylating enzymes regulate the TGF-beta and BMP signaling pathways. Following her PhD studies, Lina received an EMBO fellowship for her postdoctoral research in the lab of Ivan Dikic to work on linear ubiquitylation and autophagy. After the postdoctoral work, she joined the Frankfurt Cancer Institute as a staff scientist of the cellular and biochemical analysis platform. Lina is now a team leader of the Immue Signaling program, which aims to decipher TBK1-mediated signaling in different pathologies.
Originally from Split, Croatia Sara obtained her bachelor degree of Medical Laboratory Diagnostics with Honors at University of Split. She is currently obtaining her MSc diploma in Medicine with Industrial Specialization at Aalborg University, Denmark. She joined the lab in September 2019 for a year internship for her Master’s thesis project.
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 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.