title: The unfolded protein response is a major mechanism by which LRP1 regulates Schwann cell survival after injury.
abstract: In peripheral nerve injury, Schwann cells (SCs) must survive to exert a continuing and essential role in successful nerve regeneration. Herein, we show that peripheral nerve injury is associated with activation of endoplasmic reticulum (ER) stress and the adaptive unfolded protein response (UPR). The UPR culminates in expression of C/EBP homology protein (CHOP), a proapoptotic transcription factor in SCs, unless counteracted by LDL receptor-related protein-1 (LRP1), which serves as a major activator of phosphatidylinositol 3-kinase (PI3K). Sciatic nerve crush injury in rats induced expression of the ER chaperone GRP78/BIP, reflecting an early, corrective phase of the UPR. However, when LRP1 signaling was inhibited with receptor-associated protein, PI3K activity was decreased and CHOP protein expression increased, particularly in myelinating SCs. In cultured SCs, the PKR-like ER kinase target eIF2α was phosphorylated and CHOP was induced by (1) inhibiting PI3K, (2) treating the cells with tumor necrosis factor-α (TNF-α), or (3) genetic silencing of LRP1. CHOP gene deletion in SCs decreased cell death in response to TNF-α. Furthermore, the effects of TNF-α on phosphorylated eIF2α, CHOP, and SC death were blocked by adding LRP1 ligands that augment LRP1-dependent cell signaling to PI3K. Collectively, our results support a model in which UPR-activated signaling pathways represent a major challenge to SC survival in nerve injury. LRP1 functions as a potent activator of PI3K in SCs and, by this mechanism, limits SC apoptosis resulting from increased CHOP expression in nerve injury.
authors.affiliation: Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093-0629, USA.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mantuano
authors.forename: Kenneth
authors.initials: K
authors.lastname: Henry
authors.forename: Tomonori
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Hiramatsu
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Yamauchi
authors.forename: Sumihisa
authors.initials: S
authors.lastname: Orita
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takahashi
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Lin
authors.forename: Steven L
authors.initials: SL
authors.lastname: Gonias
authors.forename: W Marie
authors.initials: WM
authors.lastname: Campana
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012584:Sciatic Nerve / Q000293:injuries / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects / Q000502:physiology*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D051742:Transcription Factor CHOP; D014409:Tumor Necrosis Factor-alpha; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; C000717248:Hspa5 protein, mouse