The Unfolded Protein Response Is a Major Mechanism by Which LRP1 Regulates Schwann Cell Survival after Injury

Mantuano, Elisabetta; Henry, Kenneth W.; Yamauchi, Tomonori; Hiramatsu, Naoki; Yamauchi, Kazuyo; Orita, Sumihisa; Takahashi, Kazuhisa; Lin, Jonathan H.; Gonias, Steven L.; Campana, W. Marie

doi:10.1523/jneurosci.2850-11.2011

Cited by 51 publications

(44 citation statements)

References 76 publications

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“…TNF-α induces a robust up-regulation of eIF2α phosphorylation in cultured cells and in the nervous system via activation of PKR (32)(33)(34)(35)(36). Because TNF-α is a major proinflammatory cytokine (37)(38)(39)(40), which plays a critical role in the pathogenesis of inflammatory pain (41,42), we examined whether inflammationinduced TNF-α promotes eIF2α phosphorylation.…”

Section: Pkr-mediated Eif2α Phosphorylation Contributes To Thermalmentioning

confidence: 99%

eIF2α phosphorylation controls thermal nociception

Khoutorsky

Sorge

Prager‐Khoutorsky

et al. 2016

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

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A response to environmental stress is critical to alleviate cellular injury and maintain cellular homeostasis. Eukaryotic initiation factor 2 (eIF2) is a key integrator of cellular stress responses and an important regulator of mRNA translation. Diverse stress signals lead to the phosphorylation of the α subunit of eIF2 (Ser51), resulting in inhibition of global protein synthesis while promoting expression of proteins that mediate cell adaptation to stress. Here we report that eIF2α is instrumental in the control of noxious heat sensation. Mice with decreased eIF2α phosphorylation (eIF2α) exhibit reduced responses to noxious heat. Pharmacological attenuation of eIF2α phosphorylation decreases thermal, but not mechanical, pain sensitivity, whereas increasing eIF2α phosphorylation has the opposite effect on thermal nociception. The impact of eIF2α phosphorylation (p-eIF2α) on thermal thresholds is dependent on the transient receptor potential vanilloid 1. Moreover, we show that induction of eIF2α phosphorylation in primary sensory neurons in a chronic inflammation pain model contributes to thermal hypersensitivity. Our results demonstrate that the cellular stress response pathway, mediated via p-eIF2α, represents a mechanism that could be used to alleviate pathological heat sensation.pain | eIF2α | cellular stress response pathway | TRPV1 R esponse to stress is a major cellular function involved in many physiological and pathological conditions. Cells respond to various forms of stress by activating specific molecular cascades that orchestrate antistress responses or induce apoptosis (1). A key effector of cellular stress responses is the eukaryotic initiation factor 2 (eIF2) (2). Phosphorylation of eIF2 causes a reduction in global translation, allowing cells to conserve energy and modify gene expression to effectively manage stress conditions. Diverse stress signals converge onto eIF2 to integrate stress responses through phosphorylation of the α subunit of eIF2.eIF2 binds GTP and the initiator methionyl-tRNA (Met-tRNA i ) to form the ternary complex (eIF2-GTP-Met-tRNA i ). The ternary complex binds the small ribosomal subunit to form the ribosomal preinitiation complex, which scans the 5′UTR of the mRNA for the start codon to initiate mRNA translation (3). On engagement of the initiation codon, GTP is hydrolyzed to GDP (4). The recycling of inactive GDP-bound eIF2 to the active GTP-bound form is catalyzed by the guanine nucleotide exchange factor, eIF2B. Phosphorylation of the α subunit of eIF2 at serine 51 converts eIF2 from a substrate to a competitive inhibitor of eIF2B (4). Because the amount of eIF2B is lower than eIF2, phosphorylation of a small fraction of the eIF2 in the cell is sufficient to strongly inhibit eIF2B activity and translation initiation. eIF2α is phosphorylated by four eIF2α kinases, each activated in a different stress condition (5-7). PKR (double-stranded RNA-dependent protein kinase) is activated by double-stranded RNA during viral infection; PERK (PKR-like ER kinase) by endoplasmic ret...

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Section: Pkr-mediated Eif2α Phosphorylation Contributes To Thermalmentioning

confidence: 99%

eIF2α phosphorylation controls thermal nociception

Khoutorsky

Sorge

Prager‐Khoutorsky

et al. 2016

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

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“…Cell extracts were prepared using a total protein extraction kit (Millipore). An equivalent amount of cellular protein (20 -50 g/lane) was subjected to SDS-PAGE, immunoblotting, and densitometry, as described previously (11,12). Primary antibodies used included pTrkC (1:1000, Syd Laboratories), tTrkC (Abcam), pERK or total ERK (1:1000, Cell Signaling Technology).…”

Section: Cell Signaling Studies In Primary Adult Drg Neuronsmentioning

confidence: 99%

“…LRP1 agonists activate cell signaling by tyrosine phosphorylation of NPXY motifs present in the LRP1 cytoplasmic domain and by binding of signaling adaptor proteins such as Shc and JNK-interacting protein (JIP) (9,10). In Schwann cells, LRP1 activates PI3K/Akt-mediated cell survival signaling pathways and counteracts endoplasmic reticulum stress (11,12). LRP1 also interacts with other receptors, including integrins (13), platelet-derived growth factor receptors (14), and urokinase-type plasminogen activator receptor (15).…”

mentioning

confidence: 99%

Low-density Lipoprotein Receptor-related Protein 1 (LRP1)-dependent Cell Signaling Promotes Axonal Regeneration

Yoon¹,

Niekerk²,

Henry³

et al. 2013

Journal of Biological Chemistry

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Background: LRP1 activation is neuroprotective in vitro. The role of LRP1 in axonal plasticity and regeneration is unknown. Results: LRP1-dependent cell signaling that includes TrkC activation promotes axonal growth in the CNS. Conclusion: LRP1 agonists promote regeneration after spinal cord injury. Significance: A significant role is established for LRP1 in axonal growth and regeneration after CNS injury, identifying a novel class of therapeutic targets for neurological disorders.

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“…Activated Schwann cells carry out functions that are essential for nerve repair, including phagocytosis of debris, secretion of trophic factors and deposition of provisional extracellular matrix proteins. LRP1 is expressed by Schwann cells mainly after peripheral nervous system (PNS) injury (Campana et al, 2006) and functions as a robust cell signaling receptor (Mantuano et al, 2008a(Mantuano et al, ,b, 2010(Mantuano et al, , 2011. LRP1-initiated cell signaling supports Schwann cell survival and migration.…”

Section: Introductionmentioning

confidence: 99%

The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration

Mantuano

Lam

Shibayama

et al. 2015

Journal of Cell Science

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NMDA receptors (NMDA-Rs) are ionotropic glutamate receptors, which associate with LDL-receptor-related protein-1 (LRP1) to trigger cell signaling in response to protein ligands in neurons. Here, we demonstrate for the first time that the NMDA-R is expressed by rat Schwann cells and functions independently and with LRP1 to regulate Schwann cell physiology. The NR1 (encoded by GRIN1) and NR2b (encoded by GRIN2B) NMDA-R subunits were expressed by cultured Schwann cells and upregulated in sciatic nerves following crush injury. The ability of LRP1 ligands to activate ERK1/2 (also known as MAPK3 and MAPK1, respectively) and promote Schwann cell migration required the NMDA-R. NR1 gene silencing compromised Schwann cell survival. Injection of the LRP1 ligands tissue-type plasminogen activator (tPA, also known as PLAT) or MMP9-PEX into crush-injured sciatic nerves activated ERK1/2 in Schwann cells in vivo, and the response was blocked by systemic treatment with the NMDA-R inhibitor MK801. tPA was unique among the LRP1 ligands examined because tPA activated cell signaling and promoted Schwann cell migration by interacting with the NMDA-R independently of LRP1, albeit with delayed kinetics. These results define the NMDA-R as a Schwann cell signaling receptor for protein ligands and a major regulator of Schwann cell physiology, which may be particularly important in peripheral nervous system (PNS) injury.

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The Unfolded Protein Response Is a Major Mechanism by Which LRP1 Regulates Schwann Cell Survival after Injury

Cited by 51 publications

References 76 publications

eIF2α phosphorylation controls thermal nociception

eIF2α phosphorylation controls thermal nociception

Low-density Lipoprotein Receptor-related Protein 1 (LRP1)-dependent Cell Signaling Promotes Axonal Regeneration

The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration

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