Fatty acylation in health and disease
In addition to click chemistry, S-acylation (more commonly referred to as palmitoylation) can be detected using the acyl-exchange assays, which exploit the reversibility of the labile thioester bond and allows for the exchange of palmitate for thiol-reactive biotin or beads for affinity purification and detection by western or mass spectrometry. Together, these non-radioactive affinity-based detection methods spurred a plethora of S-palmitoyl-proteomic studies. Together, Dr. Shaun Sanders and I compiled all the proteomic studies up to 2014 and used an unbiased bioinformatic approach to determine what cell biology pathways and diseases are enriched in S-palmitoylated proteins (Sanders & Martin et al). Here, we found that S-palmitoylation was enriched in cancer and neurodegenerative diseases including ALS, TDP-43 proteinopathies, proteostasis deficiencies, and Huntington Disease (HD). This research is highly cited in the literature. In contrast, we have found that loss of S-palmitoylation of mutant huntingtin is linked to toxicity in HD. Restoring S-palmitoylation of mutant huntingtin is protective in HD (Lemarié et al). More recently, my lab has shown that there is a toxic interaction between ALS-causing mutations of Valosin-Containing protein (VCP) and its co-factor Small VCP-interacting protein (SVIP) that is dependent on SVIP N-myristoylation and S-palmitoylation. Co-expression of SVIP with R155H or A232E-VCP led to rapid cell death in heterologous cells and primary neuronal cultures from wild-type mice. Blocking SVIP acylation completely ameliorated this toxic effect suggesting a novel target for ALS and VCP diseases.
Ramzan, F, Abrar, F, Kumar, A, Liao, LM, Campbell, ZE, Gray, RV, Akanni, O, Guyn, CM, Martin, D.D.O. Fatty links between multisystem proteinopathy and Small VCP-Interacting Protein Under Revision at Cell Death Discovery.
Ramzan, F, Abrar, F, Mishra, GG, Liao, LM, Martin, DDO (2023) Lost in traffic: consequences of altered palmitoylation in neurodegeneration. Frontiers in Physiology
Lemarié, FL, Sanders, SS, Nguyen, YTN, Martin, DDO*, Hayden, M.R.* (2023) Full-length huntingtin is palmitoylated at multiple sites and post-translationally myristoylated following caspase-cleavage. Frontiers in Physiology doi: 10.3389/fphys.2023.1086112
Lemarié, FL, Schmidt, ME, Caron, N, Sanders, SS, Nguyen, YTN, Ko, S, Xu, X, Pouladi, MA, Martin, DDO, Hayden, MR (2021) Rescue of aberrant huntingtin palmitoylation ameliorates mutant huntingtin-induced toxicity. Neurobiology of Disease Volume 158(105479). PMID: 34390831 Available on BioRxiv
Sanders, SS*, Martin, DDO*1, Butland, S, Lavallée-Adam, M, Calzolari, D, Kay, C, Yates, JR, Hayden, MR (2015) Assembly of the mammalian palmitoylome indicates a pivotal role for palmitoylation in neurodegeneration and cancer. 11(8): e1004405. PLoS Comp Bio PMID: 26275289
Bhavsar, AP, Brown, NF, Stoepel, J, Wiermer, M, Martin, DDO, Hsu, KJ, Imami, K, Ross, CJ, Hayden, MR, Foster, LJ, Li, X, Hieter, P, Finlay, BB (2013) The Salmonella type III effector, SspH2 specifically exploits the NLR co-chaperone activity of SGT1 to subvert immunity. PLoS Pathogens 9(7): e1003518. doi:10.1371/journal.ppat.1003518 PMID: 23935490