Inositol polyphosphate multikinase promotes Toll-like receptor–induced inflammation by stabilizing TRAF6

Kim, Eunha; Beon, Jiyoon; Lee, Seulgi; Park, Seung Ju; Ahn, Hyoungjoon; Kim, Min; Park, Jeong Eun; Kim, Wooseob; Yuk, Jae–Min; Kang, Suk‐Jo; Lee, Seung‐Hyo; Jo, Eun-Kyeong; Seong, Rho Hyun; Kim, Se-Yun

doi:10.1126/sciadv.1602296

Cited by 42 publications

(41 citation statements)

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“…These results are consistent with the proliferative defects of IPMK-deficient B cells, implying that they are defective in both the signaling pathways. Recently, IPMK has been shown to promote TLR4 signaling by stabilizing TRAF6 in macrophages (38). IPMK-deficient macrophages showed increased proteasomal degradation of TRAF6, thereby, reducing TLR4-dependent proinflammatory cytokine production.…”

Section: Discussionmentioning

confidence: 99%

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Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase

Kim

Min

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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T cell-independent (TI) B cell response is critical for the early protection against pathogen invasion. The regulation and activation of Bruton’s tyrosine kinase (Btk) is known as a pivotal step of B cell antigen receptor (BCR) signaling in TI humoral immunity, as observed in patients with X-linked agammaglobulinemia (XLA) experiencing a high incidence of encapsulated bacterial infections. However, key questions remain as to whether a well-established canonical BCR signaling pathway is sufficient to regulate the activity of Btk. Here, we find that inositol hexakisphosphate (InsP6) acts as a physiological regulator of Btk in BCR signaling. Absence of higher order inositol phosphates (InsPs), inositol polyphosphates, leads to an inability to mount immune response against TI antigens. Interestingly, the significance of InsP6-mediated Btk regulation is more prominent in IgM+plasma cells. Hence, the present study identifies higher order InsPs as principal components of B cell activation upon TI antigen stimulation and presents a mechanism for InsP-mediated regulation of the BCR signaling.

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Section: Discussionmentioning

confidence: 99%

“…S7). We also examined the TRAF6 protein levels, which were found to be down-regulated in IPMKdeficient macrophages (38), but found no changes when IPMK was deleted in B cells (SI Appendix, Fig. S8).…”

Section: Ipmk Deficiency Impairs B Cell Proliferation During a Responmentioning

confidence: 99%

Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase

Kim

Min

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…IPMK has been shown to mediate LKB1 regulation of AMPK by directly interacting with AMPK, which prevents AMPK phosphorylation and activation in response to several metabolic signals, including glucose 14 , 15 and metformin 16 . Further, IPMK binds and stabilizes the TRAF6 ubiquitin ligase signaling scaffold in macrophages, preventing ubiquitination of the TRAF6 protein to maintain signaling 17 . Thus, these important studies have established several roles IPMK plays via kinase-dependent and –independent mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Crystallographic and kinetic analyses of human IPMK reveal disordered domains modulate ATP binding and kinase activity

Seacrist

Blind

2018

Sci Rep

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Inositol polyphosphate multikinase (IPMK) is a member of the IPK-superfamily of kinases, catalyzing phosphorylation of several soluble inositols and the signaling phospholipid PI(4,5)P2 (PIP2). IPMK also has critical non-catalytic roles in p53, mTOR/Raptor, TRAF6 and AMPK signaling mediated partly by two disordered domains. Although IPMK non-catalytic functions are well established, it is less clear if the disordered domains are important for IPMK kinase activity or ATP binding. Here, kinetic and structural analyses of an engineered human IPMK lacking all disordered domains (ΔIPMK) are presented. Although the KM for PIP2 is identical between ΔIPMK and wild type, ΔIPMK has a 1.8-fold increase in kcat for PIP2, indicating the native IPMK disordered domains decrease IPMK activity in vitro. The 2.5 Å crystal structure of ΔIPMK is reported, confirming the conserved ATP-grasp fold. A comparison with other IPK-superfamily structures revealed a putative “ATP-clamp” in the disordered N-terminus, we predicted would stabilize ATP binding. Consistent with this observation, removal of the ATP clamp sequence increases the KM for ATP 4.9-fold, indicating the N-terminus enhances ATP binding to IPMK. Together, these structural and kinetic studies suggest in addition to mediating protein-protein interactions, the disordered domains of IPMK impart modulatory capacity to IPMK kinase activity through multiple kinetic mechanisms.

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“…For example, deletion of IPMK in mouse embryonic fibroblasts reduced Akt kinase signaling by interrupting the PI-3 kinase activity of IPMK (4). In addition to its catalytic role in inositol phosphate metabolism, IPMK noncatalytically regulates major signaling factors, including mechanistic target of rapamycin (mTOR), p53, serum response factor, and tumor necrosis factor receptor-associated factor 6 (5)(6)(7)(8). In mammalian cells, therefore, IPMK coordinates the activity of diverse signaling networks involved in gene expression, growth, metabolism, and innate immunity (9)(10)(11).…”

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confidence: 99%

Inositol polyphosphate multikinase mediates extinction of fear memory

Park

Longo

Park

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Inositol polyphosphate multikinase (IPMK), the key enzyme for the biosynthesis of higher inositol polyphosphates and phosphatidylinositol 3,4,5-trisphosphate, also acts as a versatile signaling player in regulating tissue growth and metabolism. To elucidate neurobehavioral functions of IPMK, we generated mice in which IPMK was deleted from the excitatory neurons of the postnatal forebrain. These mice showed no deficits in either novel object recognition or spatial memory. IPMK conditional knockout mice formed cued fear memory normally but displayed enhanced fear extinction. Signaling analyses revealed dysregulated expression of neural genes accompanied by selective activation of the mechanistic target of rapamycin (mTOR) regulatory enzyme p85 S6 kinase 1 (S6K1) in the amygdala following fear extinction. The IPMK mutants also manifested facilitated hippocampal long-term potentiation. These findings establish a signaling action of IPMK that mediates fear extinction.inositol polyphosphate multikinase | memory | fear extinction | long-term potentiation I nositol polyphosphate multikinase (IPMK) is a pleiotropic protein. As an enzyme, it catalyzes the production of watersoluble inositol polyphosphates (IPs), such as inositol 1,4,5,6tetrakisphosphate [Ins(1,4,5,6)P 4 ] (1, 2) and lipid-bound phosphatidylinositol 3,4,5-triphosphates (3, 4). The catalytic products of IPMK directly influence downstream target proteins. For example, deletion of IPMK in mouse embryonic fibroblasts reduced Akt kinase signaling by interrupting the PI-3 kinase activity of IPMK (4). In addition to its catalytic role in inositol phosphate metabolism, IPMK noncatalytically regulates major signaling factors, including mechanistic target of rapamycin (mTOR), p53, serum response factor, and tumor necrosis factor receptor-associated factor 6 (5-8). In mammalian cells, therefore, IPMK coordinates the activity of diverse signaling networks involved in gene expression, growth, metabolism, and innate immunity (9-11). In a previous study, our group reported that the conditional Ipmk knockout during the early embryonic stage of neurodevelopment by using Nestin-Cre transgenic mice blunted the response of immediate early genes to electroconvulsive stimuli and exhibited a spatial memory deficit under the Barnes maze test (12). However, nothing is known of IPMK's physiologic impact on neural functions in the context of specific neuronal cell types.Memory of fearful events forms quickly and is difficult to erase. In rodent models, fear can be created via Pavlovian conditioning paradigms, in which a biologically neutral stimulus (such as a tone) or context (conditioned stimulus, or CS) is paired with an aversive, unconditioned stimulus (US, such as a footshock). The memory of the CS-US association is robust and long-lasting, but if the CS is repeatedly presented in the absence of the US, the fear response is gradually reduced through a process known as extinction (13,14). Extinction of fear memory is learned by the formation of new memories that suppress conditi...

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Inositol polyphosphate multikinase promotes Toll-like receptor–induced inflammation by stabilizing TRAF6

Abstract: Inositol polyphosphate multikinase acts as a key determinant of inflammation by stabilizing the signaling adaptor TRAF6.

Cited by 42 publications

References 64 publications

Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase

Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton’s tyrosine kinase

Crystallographic and kinetic analyses of human IPMK reveal disordered domains modulate ATP binding and kinase activity

Inositol polyphosphate multikinase mediates extinction of fear memory

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