Protein S-Acylation, Cell Signaling, Calcium Regulation, Cancer, Immunity
Protein S-acylation is a reversible post-translational modification of cysteine residues by a variety of fatty acid species. Although protein S-acylation was discovered more than 30 years ago and S-acylated proteins have been implicated in pathogenesis of several diseases including cancer, cardiovascular and immune disorders, it remains one of the most understudied post-translational protein modifications. High lability, one of the key features of protein S-acylation, along with its prominent effect on the protein function, makes it an attractive mechanism for the regulation of intracellular signaling. In particular, rapid changes in the protein palmitoylation (S-acylation with a palmitic acid moiety) status could provide a molecular basis for activation of plasma membrane-localized signaling proteins by targeting them into specific plasma membrane subdomains.
We propose a model in which the engaged TCR complex recruits and activates plasma membrane-associated PATs to increase palmitoylation of key signaling proteins. We aim our studies (a) to analyze the dynamics and regulation of stimulus-dependent palmitoylation of Lck, LAT and other members of TCR signaling pathway and (b) to uncover a previously uncharacterized role of DHHC PATs in the regulation of T cell signaling. We expect that inclusion of a novel class of regulatory enzymes into the canonical TCR signaling pathway would greatly expand the range of potential therapeutic targets for diseases associated with altered T cell homeostasis.
Akimzhanov AM, Boehning D. 2015. Rapid and transient palmitoylation of the tyrosine kinase Lck mediates Fas signaling. Proc Natl Acad Sci USA. 112(38):11876-80.
Akimzhanov AM, Barral JM, Boehning D. 2013. Caspase 3 Cleavage of the Inositol 1,4,5-Trisphosphate Receptor Does Not Contribute to Apoptotic Calcium Release. Cell Calcium. 53(2):152-8.
Akimzhanov AM, Wang X, Sun J, Boehning D. 2010. T-cell receptor complex is essential for Fas signal transduction. Proc Natl Acad Sci USA. 107(34):15105-10.
Akimzhanov A, Krenacs L, Schlegel T, Klein-Hessling S, Bagdi E, Stelkovics E, Kondo E, Chuvpilo S, Wilke P, Avots A, Gattenlohner S, Muller-Hermelink HK, Palmetshofer A, Serfling E. 2008. Epigenetic changes and suppression of the nuclear factor of activated T cell 1 (NFATC1) promoter in human lymphomas with defects in immunoreceptor signaling. Am J Pathol. 172(1):215-24.
Akimzhanov AM, Yang XO, Dong C. 2007. Chromatin remodeling of interleukin-17 (IL-17)-IL-17F cytokine gene locus during inflammatory helper T cell differentiation. J Biol Chem. 282(9):5969-72.