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

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