Biography

Post-translational Modifications (PTMs) Driving Inflammatory Disease

Genome-wide association studies (GWAS) and next-generation sequencing technologies (NGS) have greatly expanded our knowledge of disease-associated genetic variants. However, for many of these variants, the underlying molecular mechanisms and cellular pathways influencing disease development are, yet, unknown. One avenue that can contribute to the functional understanding of such disease-related associations is the study of post-translational modifications (PTMs). PTM involves the attachment of biochemical functional groups or moieties, often affecting a protein’s localization, stability, and function. Determining how a disease-associated variant influences or is influenced by PTMs is an appealing strategy not only because it may give insight into a protein’s regulation and function, and therefore, point to involvement of a certain biological pathway, but also, as many PTMs are enzymatically regulated, it allows for pharmaceutical targeting of such PTMs. Therefore, identifying and understanding the roles of PTMs in various disease states will be important if one wants to determine an underlying molecular defect, identify a novel drug target, and manipulate signaling pathways for clinical benefit.

Majority of my work will focus on signaling mediated through the bacterial peptidoglycan sensor NOD2. Our research on this pathway has led to the discovery that RIP2, the NOD2-associated kinase, undergoes inducible tyrosine autophosphorylation. This led to the identification of RIP2 as the tyrosine kinase mediating this PTM, reclassifying it as a dual-specificity kinase. These findings encouraged us to conduct a small molecule screen for inhibitors of RIP2’s tyrosine kinase activity, a direction which led to the identification of FDA-approved drugs (Erlotinib and Gefitinib) which could be repurposed for inhibiting NOD2/RIP2 hyperactive states such as asthma, EAE, arthritis, and certain settings of IBD (WT NOD2 background). My latest work demonstrates that targeting RIP2’s kinase activity in vivo (using Gefitinib or a novel RIP2 specific inhibitor) is protective in three inflammatory disease states: a spontaneous ileitis model, a DSS colitis model, and an MDP-induced peritonitis model. I am also currently funded to understand how RIP2 may play a role in the pathogenesis of allergic asthma. These studies nicely illustrate the feasibility, broad applicability and clinical relevance of studying PTMs in inflammatory disease, a direction which I hope to continue in the future.

Recent Publications

Tigno-Aranjuez, J.T., Benderitter, P., Rombouts, F., Deroose, F., Bai, X., Mattioli, B., Cominelli, F., Pizarro, T.T., Hoflack, J., and D.W. Abbott. “In vivo inhibition of RIP2 kinase alleviates inflammatory disease”. J. Biol. Chem. 2014. 289:29651-64.

Jun, J., Kertesy, S., Jones, M., Marinis, J.M., Cobb, B.A., Tigno-Aranjuez, J.T. and D.W. Abbott. “Innate immune-directed NF-κB signaling requires site-specific NEMO ubiquitination”. Cell Reports. 2013. 4:352-61.

Tigno-Aranjuez, J.T. and D.W. Abbott. “Transcriptomics identifies a discrete ubiquitin-regulated network driving NOD2-dependent signaling”. Mol. Cell. Biol. 2013. 33:146-58

Tigno-Aranjuez, J.T. and D.W. Abbott. “Ubiquitination and Phosphorylation in the Regulation of NOD2 signaling and NOD2-mediated Disease”. Biochim Biophys Acta. 2012. 1823:2022-8

Tigno-Aranjuez, J.T., Asara, J.M., and D.W. Abbott. “Inhibition of RIP2’s tyrosine kinase activity limits NOD2-driven cytokine responses”. Genes Dev. 2010. 24:2666-77.