Aminoacyl-tRNA Synthetase-Interacting Multifunctional Protein 1/p43 Controls Endoplasmic Reticulum Retention of Heat Shock Protein gp96

Han, Jung Min; Park, Sang Gyu; Liu, Bei; Park, Bum-Joon; Kim, Jin Young; Jin, Cheng; Song, Yeong Wook; Li, Zihai; Kim, Sung Hoon

doi:10.2353/ajpath.2007.061266

Cited by 41 publications

(49 citation statements)

References 68 publications

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“…There is accumulating evidence for the multiple functions of MSC p43, including extracellular function as a cytokine for monocytes, endothelial cells, and fibroblasts and as a glucagonlike hormone (23) and intracellular function in activating immune dendritic cells (19). However, the role of MSC p43 in the adult CNS has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

“…To unravel the potential biological function of MSC p43 in the CNS, we examined the behaviors of MSC p43-deficient mice (18,19). Most MSC p43-null mice displayed weight loss, decreased fertility and grooming, and spontaneous and sometimes spastic tremors, although the severity and onset of the symptoms (about 1 month after birth) were variable among littermates.…”

Section: Characterization Of Msc P43 Expression In the Cnsmentioning

confidence: 99%

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MSC p43 required for axonal development in motor neurons

Zhu

Liu

Yin

et al. 2009

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

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Neuron connectivity and correct neural function largely depend on axonal integrity. Neurofilaments (NFs) constitute the main cytoskeletal network maintaining the structural integrity of neurons and exhibit dynamic changes during axonal and dendritic growth. However, the mechanisms underlying axonal development and maintenance remain poorly understood. Here, we identify that multisynthetase complex p43 (MSC p43) is essential for NF assembly and axon maintenance. The MSC p43 protein was predominantly expressed in central neurons and interacted with NF light subunit in vivo. Mice lacking MSC p43 exhibited axon degeneration in motor neurons, defective neuromuscular junctions, muscular atrophy, and motor dysfunction. Furthermore, MSC p43 depletion in mice caused disorganization of the axonal NF network. Mechanistically, MSC p43 is required for maintaining normal phosphorylation levels of NFs. Thus, MSC p43 is indispensable in maintaining axonal integrity. Its dysfunction may underlie the NF disorganization and axon degeneration associated with motor neuron degenerative diseases.assembly ͉ axon degeneration ͉ multisynthetase complex ͉ neurofilament T he development and maintenance of neuronal axons are essential for the establishment of neuron connectivity and for correct neural function. Neurofilaments (NFs), a subtype of intermediate filaments (IFs), form part of the cytoskeleton that confers the intracellular scaffold and mechanical stability of neurons (1, 2). They are dynamic structures known to play key roles in neuronal development and function, such as neuronal morphogenesis, neuronal migration, axonal growth, synaptic plasticity, and intracellular transport (3). Five major types of IF proteins are expressed in adult neurons: 3 neurofilament proteins [neurofilament-light subunit (NF-L), neurofilamentmedium subunit (NF-M), and neurofilament-heavy subunit (NF-H), peripherin, and ␣-internexin (3). Studies with either gene targeting or a transgenic approach provide evidence that deficiency of NF proteins and disorganization of the neuronal NF network can result in abnormalities in the motor axon caliber, defective axonal transport, axon atrophy and loss, and motor dysfunction (3). Despite the abundance and crucial role of NFs in neurons, the molecular basis for the development and maintenance of neuronal axons is not fully understood.Posttranslational modifications and binding partners are keys for regulation of the dynamics and functions of NFs. Phosphorylation takes center stage for their regulation (4). Phosphorylation of NFs is slow and orchestrated by a range of enzymes, and NFs have been reported to be substrates of many kinases (5). The phosphorylation of NFs plays a key role in NF assembly and turnover; in forming cross-bridges between NFs, actin filaments, and microtubules (MTs); in axonal transport of NFs themselves; and in promoting NF integration into the cytoskeleton underlying dendrite arborization and axonal caliber determination and stability (4, 6, 7). Studies with transgenic mice overexpressing N...

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Section: Discussionmentioning

confidence: 99%

Section: Characterization Of Msc P43 Expression In the Cnsmentioning

confidence: 99%

MSC p43 required for axonal development in motor neurons

Zhu

Liu

Yin

et al. 2009

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

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“…AIMP1 is also involved in diverse physiological processes (Lee et al, 2008), including extracellular cytokine activities involving monocytes (Ko et al, 2001;Park et al, 2002a;Park et al, 2002b), endothelial cells (Park et al, 2002c), and fibroblasts (Park et al, 2005), and glucagon-like hormonal activity . We recently reported that the intracellular physical interaction between AIMP1 and gp96 controls the ER retention of gp96, thereby preventing its extracellular presentation (Han et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Identification of CD23 as a functional receptor for the proinflammatory cytokine AIMP1/p43

Kwon¹,

Park²,

Kim³

et al. 2012

Journal of Cell Science

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SummaryAminoacyl-tRNA-synthetase-interacting multifunctional protein 1 (AIMP1/p43) can be secreted to trigger proinflammatory molecules while it is predominantly bound to a cytoplasmic macromolecular protein complex that contains several different aminoacyl-tRNA synthetases. Although its activities as a secreted signaling factor have been well characterized, the functional receptor for its proinflammatory activity has not yet identified. In this study, we have identified the receptor molecule for AIMP1 that mediates the secretion of TNF-a from THP-1 monocytic cells and primary human peripheral blood mononuclear cells (PBMCs). In a screen of 499 soluble receptors we identified CD23, a known low-affinity receptor for IgE, as a high affinity binding partner of AIMP1. We found that downregulation of CD23 attenuated AIMP1-induced TNF-a secretion and AIMP1 binding to THP-1 and PBMCs. We also observed that in THP-1 and PBMCs, AIMP1-induced TNF-a secretion, mediated by CD23, involved activation of ERK1/2. Interestingly, endothelial monocyte activating polypeptide II (EMAP II), the Cterminal fragment of AIMP1 that is also known to work as a proinflammatory cytokine, was incapable of binding to CD23 and of activating ERK1/2. Therefore, identification of CD23 not only explains the inflammatory function of AIMP1 but also provides the first evidence by which the mode of action of AIMP1 can be distinguished from that of its C-terminal domain, EMAP II.

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“…AIMP1 (p43) is secreted as a cytokine that controls angiogenesis , immune response (Ko et al, 2001; and tissue regeneration (Park S. G. et al, 2005b), and also as a hormone for glucose homeostasis . It is also implicated in the regulation of autoimmune phenotype such as lupus (Han et al, 2007). AIMP3 (p18) was demonstrated to be a tumor suppressor responding to DNA damage Park B. J. et al, 2005) or oncogenic stimuli (Park B. J. et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

AIMP2 promotes TNFα-dependent apoptosis via ubiquitin-mediated degradation of TRAF2

Choi

Kim

Park

et al. 2009

Journal of Cell Science

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AIMP2 (aminoacyl-tRNA synthetase interacting multifunctional protein 2; also known as JTV-1) was first identified as p38 in a macromolecular protein complex that consisted of nine different aminoacyl-tRNA synthetases and two other auxiliary factors. AIMP2 also plays pivotal roles in the regulation of cell proliferation and death. Although AIMP2 was previously shown to augment TNFα-induced cell death, its working mechanism in this signal pathway was not understood. Here, we investigate the functional significance and mode of action of AIMP2 in TNFα signaling. TNFα-induced cell death was compromised in AIMP2-deficient or -suppressed cells and exogenous supplementation of AIMP2 augmented apoptotic sensitivity to TNFα signaling. This activity was confirmed by the AIMP2-dependent increase of IκB and suppression of NFκB. We found binding of AIMP2 to TRAF2, a key player in the TNFα signaling pathway. AIMP2 augmented the association of an E3 ubiquitin ligase, c-IAP1, with TRAF2, causing ubiquitin-dependent degradation of TRAF2. These findings suggest that AIMP2 can mediate the pro-apoptotic activity of TNFα via the downregulation of TRAF2 expression.

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Aminoacyl-tRNA Synthetase-Interacting Multifunctional Protein 1/p43 Controls Endoplasmic Reticulum Retention of Heat Shock Protein gp96

Cited by 41 publications

References 68 publications

MSC p43 required for axonal development in motor neurons

MSC p43 required for axonal development in motor neurons

Identification of CD23 as a functional receptor for the proinflammatory cytokine AIMP1/p43

AIMP2 promotes TNFα-dependent apoptosis via ubiquitin-mediated degradation of TRAF2

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