Toll-like receptor mediated inflammation requires FASN-dependent MYD88 palmitoylation

Kim, Young Chan; Lee, Sang-Eun; Kim, Somi K.; Jang, Hyun Duk; Hwang, Injoo; Jin, Shaohua; Hong, Eun Byeol; Jang, Kyoung-Soon; Kim, Hyo Soo

doi:10.1038/s41589-019-0344-0

Cited by 103 publications

(121 citation statements)

References 56 publications

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“…TLR signaling has previously been shown to be activated by saturated fatty acids even though fatty acids do not bind to TLR, suggesting a ligand-independent TLR activation meditated by fatty acids (Fessler et al, 2009;Lancaster et al, 2018). Further study reveals that MyD88, an adaptor molecule of TLR signaling, is palmitoylated by DHHC6 at Cys113 (Kim et al, 2019). The palmitoylation of MyD88 is required for its binding to IRAK4 and activation of downstream NF-κB.…”

Section: Toll-like Receptors/myd88 Signalingmentioning

confidence: 84%

“…Reducing intracellular palmitate concentration by the inhibition of de novo fatty acid synthesis blocks LPS-induced neutrophil activation and MyD88-dependent cytokine production. The critical roles of palmitoylation in TLR/MyD88 signaling is further supported by the fact that the DHHC inhibitor 2-bromopalmitate (2-BP) inhibits NF-κB activation, whereas the APT inhibitor palmostatin B enhances the activation of NF-κB (Kim et al, 2019). In fact, many isotypes of TLRs (TLR 2,5,6,10) are shown to be palmitoylated in other types of leukocytes, which will be discussed in detail later.…”

Section: Toll-like Receptors/myd88 Signalingmentioning

confidence: 92%

“…For example, mice with DHHC21 deficiency display a reduced number of slow-rolling and adherent leukocytes in post-capillary venules during systemic inflammation (Beard et al, 2016). There is evidence for DHHC6-catalyzed MyD88 palmitoylation in neutrophils, which is necessary for TLR-NF-κB signaling (Kim et al, 2019). In dendritic cells, surface expression and proper function of TLR2 depend on the palmitoylation of TLR2 by DHHC 2, 3, 6, 7, or 15 (Chesarino et al, 2014).…”

Section: Palmitoyl Acyltransferasesmentioning

confidence: 99%

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Protein Palmitoylation in Leukocyte Signaling and Function

Yang

Chatterjee

et al. 2020

Front. Cell Dev. Biol.

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Palmitoylation is a post-translational modification (PTM) based on thioester-linkage between palmitic acid and the cysteine residue of a protein. This covalent attachment of palmitate is reversibly and dynamically regulated by two opposing sets of enzymes: palmitoyl acyltransferases containing a zinc finger aspartate-histidine-histidine-cysteine motif (PAT-DHHCs) and thioesterases. The reversible nature of palmitoylation enables fine-tuned regulation of protein conformation, stability, and ability to interact with other proteins. More importantly, the proper function of many surface receptors and signaling proteins requires palmitoylation-meditated partitioning into lipid rafts. A growing number of leukocyte proteins have been reported to undergo palmitoylation, including cytokine/chemokine receptors, adhesion molecules, pattern recognition receptors, scavenger receptors, T cell co-receptors, transmembrane adaptor proteins, and signaling effectors including the Src family of protein kinases. This review provides the latest findings of palmitoylated proteins in leukocytes and focuses on the functional impact of palmitoylation in leukocyte function related to adhesion, transmigration, chemotaxis, phagocytosis, pathogen recognition, signaling activation, cytotoxicity, and cytokine production.

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Section: Toll-like Receptors/myd88 Signalingmentioning

confidence: 84%

Section: Toll-like Receptors/myd88 Signalingmentioning

confidence: 92%

Section: Palmitoyl Acyltransferasesmentioning

confidence: 99%

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Protein Palmitoylation in Leukocyte Signaling and Function

Yang

Chatterjee

et al. 2020

Front. Cell Dev. Biol.

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“…The previous studies support that saturated free fatty acids exert proinflammatory roles through the TLR4 in multiple cell types including monocytes, macrophages, adipocytes and chondrocytes [ 22 , 36 , 37 , 38 , 39 , 40 , 41 ]. TLR4-downstream signaling involves either MyD88-or TRIF/TBK1 related adaptor molecules [ 42 , 43 ]. Verstak et al reported a novel role for Toll-receptor-associated molecule (TRAM) in TLR4-mediated signaling via its interaction with tumor-necrosis factor receptor-associated factor 6 (TRAF6), distinct from its role as a bridging adaptor between TLR4 and TRIF [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

“…Our results showed that MyD88 deficiency did not block the cooperative effects of stearic acid on MIP-1α/CCL3 production. Though MyD88 is a critical adaptor protein for TLR4 signaling related to inflammation [ 42 , 45 , 46 ]. TLR4 uses TRIF/TBK1/IKKε as other adaptor molecules to induce the expression of IFN-β in a MyD88-independent manner [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Stearic Acid and TNF-α Co-Operatively Potentiate MIP-1α Production in Monocytic Cells via MyD88 Independent TLR4/TBK/IRF3 Signaling Pathway

et al. 2020

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Increased circulatory and adipose tissue expression of macrophage inflammatory protein (MIP)-1α (CC motif chemokine ligand-3/CCL3) and its association with inflammation in the state of obesity is well documented. Since obesity is associated with increases in both stearic acid and tumor necrosis factor α (TNF-α) in circulation, we investigated whether stearic acid and TNF-α together could regulate MIP-1α/CCL3 expression in human monocytic cells, and if so, which signaling pathways were involved in MIP-1α/CCL3 modulation. Monocytic cells were treated with stearic acid and TNF-α resulted in enhanced production of MIP-1α/CCL3 compared to stearic acid or TNF-α alone. To explore the underlying mechanisms, cooperative effect of stearic acid for MIP-α/CCL3 expression was reduced by TLR4 blocking, and unexpectedly we found that the synergistic production of MIP-α/CCL3 in MyD88 knockout (KO) cells was not suppressed. In contrast, this MIP-α/CCL3 expression was attenuated by inhibiting TBK1/IRF3 activity. Cells deficient in IRF3 did not show cooperative effect of stearate/TNF-α on MIP-1α/CCL3 production. Furthermore, activation of IRF3 by polyinosinic-polycytidylic acid (poly I:C) produced a cooperative effect with TNF-α for MIP-1α/CCL3 production that was comparable to stearic acid. Individuals with obesity show high IRF3 expression in monocytes as compared to lean individuals. Furthermore, elevated levels of MIP-1α/CCL3 positively correlate with TNF-α and CD163 in fat tissues from individuals with obesity. Taken together, this study provides a novel model for the pathologic role of stearic acid to produce MIP-1α/CCL3 in the presence of TNF-α associated with obesity settings.

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Deacylases—structure, function, and relationship to diseases

Wang,

Xing,

et al. 2024

FEBS Letters

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Reversible S‐acylation plays a pivotal role in various biological processes, modulating protein functions such as subcellular localization, protein stability/activity, and protein–protein interactions. These modifications are mediated by acyltransferases and deacylases, among which the most abundant modification is S‐palmitoylation. Growing evidence has shown that this rivalrous pair of modifications, occurring in a reversible cycle, is essential for various biological functions. Aberrations in this process have been associated with various diseases, including cancer, neurological disorders, and immune diseases. This underscores the importance of studying enzymes involved in acylation and deacylation to gain further insights into disease pathogenesis and provide novel strategies for disease treatment. In this Review, we summarize our current understanding of the structure and physiological function of deacylases, highlighting their pivotal roles in pathology. Our aim is to provide insights for further clinical applications.

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Toll-like receptor mediated inflammation requires FASN-dependent MYD88 palmitoylation

Cited by 103 publications

References 56 publications

Protein Palmitoylation in Leukocyte Signaling and Function

Protein Palmitoylation in Leukocyte Signaling and Function

Stearic Acid and TNF-α Co-Operatively Potentiate MIP-1α Production in Monocytic Cells via MyD88 Independent TLR4/TBK/IRF3 Signaling Pathway

Deacylases—structure, function, and relationship to diseases

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