Post-translational myristoylation at the cross roads of cell death, autophagy and neurodegeneration

Martin, Dale D.O.; Hayden, Michael R.

doi:10.1042/bst20140281

Cited by 21 publications

(20 citation statements)

References 50 publications

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“…Although the majority of N-myristoylated proteins undergo fatty acylation during protein translation, a second class of NMT substrates that are N-myristoylated post-translationally has been uncovered[15, 16]. During apoptosis, caspase-mediated cleavage between Asp-Gly exposes glycine at the N-terminus of the newly cleaved product.…”

Section: N-myristoylationmentioning

confidence: 99%

Fatty acylation of proteins: The long and the short of it

Resh

2016

Progress in Lipid Research

237

235

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Long, short and medium chain fatty acids are covalently attached to hundreds of proteins. Each fatty acid confers distinct biochemical properties, enabling fatty acylation to regulate intracellular trafficking, subcellular localization, protein-protein and protein-lipid interactions. Myristate and palmitate represent the most common fatty acid modifying groups. New insights into how fatty acylation reactions are catalyzed, and how fatty acylation regulates protein structure and function continue to emerge. Myristate is typically linked to an N-terminal glycine, but recent studies reveal that lysines can also be myristoylated. Enzymes that remove N-terminal myristoyl-glycine or myristate from lysines have now been identified. DHHC proteins catalyze S-palmitoylation, but the mechanisms that regulate substrate recognition by individual DHHC family members remain to be determined. New studies continue to reveal thioesterases that remove palmitate from S-acylated proteins. Another area of rapid expansion is fatty acylation of the secreted proteins Hedgehog, Wnt and Ghrelin, by Hhat, Porcupine and GOAT, respectively. Understanding how these membrane bound O-acyl transferases recognize their protein and fatty acyl CoA substrates is an active area of investigation, and is punctuated by the finding that these enzymes are potential drug targets in human diseases.

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Section: N-myristoylationmentioning

confidence: 99%

Fatty acylation of proteins: The long and the short of it

Resh

2016

Progress in Lipid Research

237

235

View full text Add to dashboard Cite

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“…The posttranslational myristoylation of protein was first reported in 2000, to show that N-myristoylation of BID after its being cleaved by caspase 8 targets the myristoylated BID to mitochondrial membrane that augments the cellular pro-apoptotic activity (Figure 4) (4). As initiation of apoptosis is characterized by caspase-mediated proteolytic cleavage at the preferred glycine (85, 86), it is highly plausible that myristoylation might be the common posttranslational modification following caspase-mediated proteolytic cleavage (87). It then suggests that the posttranslational myristoylation may play a key role in cell survival and apoptosis.…”

Section: Myristoylation Regulates Mitochondrial Calcium Release Activmentioning

confidence: 99%

“…Heretofore, only BID and p21-activated kinase 2 are the known substrates of posttranslational myristoylation. With the in silico prediction analysis, coupled to an overexpression system, other substrates of posttranslational myristoylation (including but not limited to gelsolin B cell receptor-associated protein 31 and YTH domain family protein) have been discovered (4, 87, 88). These in vitro identified substrates were validated using a robust proteomic technique that uses new NMT inhibitors to confirm myristoylation (89).…”

Section: Myristoylation Regulates Mitochondrial Calcium Release Activmentioning

confidence: 99%

Myristoylation: An Important Protein Modification in the Immune Response

et al. 2017

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Protein N-myristoylation is a cotranslational lipidic modification specific to the alpha-amino group of an N-terminal glycine residue of many eukaryotic and viral proteins. The ubiquitous eukaryotic enzyme, N-myristoyltransferase, catalyzes the myristoylation process. Precisely, attachment of a myristoyl group increases specific protein–protein interactions leading to subcellular localization of myristoylated proteins with its signaling partners. The birth of the field of myristoylation, a little over three decades ago, has led to the understanding of the significance of protein myristoylation in regulating cellular signaling pathways in several biological processes especially in carcinogenesis and more recently immune function. This review discusses myristoylation as a prerequisite step in initiating many immune cell signaling cascades. In particular, we discuss the hitherto unappreciated implication of myristoylation during myelopoiesis, innate immune response, lymphopoiesis for T cells, and the formation of the immunological synapse. Furthermore, we discuss the role of myristoylation in inducing the virological synapse during human immunodeficiency virus infection as well as its clinical implication. This review aims to summarize existing knowledge in the field and to highlight gaps in our understanding of the role of myristoylation in immune function so as to further investigate into the dynamics of myristoylation-dependent immune regulation.

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“…We have shown that cleavage at D552 is required to release a newly exposed N-terminal glycine at position 553 (G553) that is subsequently posttranslationally myristoylated (16)(17)(18). Myristoylation involves the covalent addition, via an amide bond, of the saturated fatty acid myristate to Nterminal glycines that directs proteins to membranes (19,20). We also recently discovered a naturally occurring missense mutation at this site wherein the essential glycine is substituted to a glutamate, thereby blocking myristoylation (17).…”

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confidence: 99%

Identification of a novel caspase cleavage site in huntingtin that regulates mutant huntingtin clearance

et al. 2018

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Huntington disease (HD) is a progressive neurodegenerative disease that initially affects the striatum and leads to changes in behavior and loss of motor coordination. It is caused by an expansion in the polyglutamine repeat at the N terminus of huntingtin (HTT) that leads to aggregation of mutant HTT. The loss of wild‐type function, in combination with the toxic gain of function mutation, initiates various cell death pathways. Wild‐type and mutant HTT are regulated by different posttranslational modifications that can positively or negatively regulate their function or toxicity. In particular, we have previously shown that caspase cleavage of mutant HTT at amino acid position aspartate 586 (D586) by caspase‐6 is critical for the pathogenesis of the disease in an HD mouse model. Herein, we describe the identification of a new caspase cleavage site at position D572 that is mediated by caspase‐1. Inhibition of caspase‐1 also appeared to decrease proteolysis at D586, likely by blocking the downstream activation of caspase‐6 through caspase‐1. Inhibition of caspase cleavage at D572 significantly decreased mutant HTT aggregation and significantly increased the turnover of soluble mutant HTT. This suggests that caspase‐1 may be a viable target to inhibit caspase cleavage of mutant HTT at both D572 and D586 to promote mutant HTT clearance.—Martin, D. D. O., Schmidt, M. E., Nguyen, Y. T., Lazic, N., Hayden, M. R. Identification of a novel caspase cleavage site in huntingtin that regulates mutant huntingtin clearance. FASEB J. 33, 3190–3197 (2019). http://www.fasebj.org

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Post-translational myristoylation at the cross roads of cell death, autophagy and neurodegeneration

Cited by 21 publications

References 50 publications

Fatty acylation of proteins: The long and the short of it

Fatty acylation of proteins: The long and the short of it

Myristoylation: An Important Protein Modification in the Immune Response

Identification of a novel caspase cleavage site in huntingtin that regulates mutant huntingtin clearance

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