Processing of HEBP1 by Cathepsin D Gives Rise to F2L, the Agonist of Formyl Peptide Receptor 3

Devosse, Thalie; Dutoit, Raphaël; Migeotte, Isabelle; Nadaï, Patricia de; Imbault, Virginie; Communi, David; Salmon, Isabelle; Parmentier, Marc

doi:10.4049/jimmunol.1003545

Cited by 22 publications

(16 citation statements)

References 57 publications

(64 reference statements)

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“…4 HEBP1 is an intracellular protein involved in heme regulation, and its proteolytic cleavage generates the F2L peptide, which is an FPR3 ligand. 27 Our observations are in accordance with the finding that peptide Hp (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), from Helicobacter pylori, promotes healing of damaged gastric mucosa by interacting with FPRs. 8 FPR ligands also stimulate the repair of colonic, lung and retinal pigment epithelial cells.…”

Section: Discussionsupporting

confidence: 92%

The formyl peptide receptor 1 exerts a tumor suppressor function in human gastric cancer by inhibiting angiogenesis

et al. 2014

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N-formyl peptide receptors (FPR1, FPR2 and FPR3) are involved in innate immunity, inflammation and cancer. FPR expression, initially described in immune cells, was later observed in non-hematopoietic cell populations and tissues. Several studies suggested a role for FPRs in the progression of various tumor histotypes, including gastric cancer (GC), for which a positive association with a specific FPR1 polymorphism has recently been described. We previously showed that FPRs are expressed on gastric epithelium and are required for wound repair and restitution of barrier integrity. Here we assess the role of FPRs in GC. We characterized the functions of FPRs in GC epithelial cells (MKN28, AGS and MKN45) cultured in vitro by assessing migration, proliferation, resistance to apoptosis and activation of the epithelial-to-mesenchymal transition. Activation of each FPR induced the epithelial-to-mesenchymal transition, proliferation, resistance to apoptosis and migration of GC cells in culture. Blocking compounds or RNA interference of each FPR reverted these effects. We also defined the in vivo tumorigenic potential of GC epithelial cells silenced for FPRs by xenograft experiments in immunocompromised mice. Interestingly, FPR1 silencing in GC cells (shFPR1) significantly enhanced xenograft growth with respect to shCTR, shFPR2 and shFPR3 xenografts, because of augmented vessel density and cell proliferation. Accordingly, HIF-1α and VEGF mRNA levels were higher in shFPR1 xenografts than in controls. Moreover, the in vitro production of proangiogenic factors in response to FPR2/3 agonists (WKYMVm, LL-37, uPA, uPAR84-95, AnxA1) or to other proinflammatory mediators (IL-1α) was higher in shFPR1 GC cells than in shCTR, shFPR2 and shFPR3 cells, suggesting that FPR1 functions as an inhibitor of CG angiogenesis. Thus, we propose that FPR1 stimulation may represent a novel therapeutic approach to counteract tumor angiogenesis.

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Section: Discussionsupporting

confidence: 92%

The formyl peptide receptor 1 exerts a tumor suppressor function in human gastric cancer by inhibiting angiogenesis

et al. 2014

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“…In addition to the known candidates, we observed a remarkable and novel enrichment of additional factors involved in antiviral state, innate immunity, and neuroinflammation (Additional file 9 : Table S7) including Gin1 (gypsy retrotransposon integrase 1) [ 91 ], Hmox1 (Heme oxygenase 1) [ 92 , 93 ], Hebp1 (Heme-binding protein 1) [ 94 ], Snx16 (Sorting nexin 16) [ 95 ], Timp1 (Tissue inhibitor of metalloproteinase 1) [ 96 , 97 ], Dnmt2 (DNA methyltransferase 2) [ 98 – 101 ], Rsad2 (Radical S-adenosyl methionine domain containing 2 = Viperin) [ 102 – 106 ], Adamts4 (a disintegrin-like and metallopeptidase—reprolysin type—with thrombospondin type 1 motif, 4) [ 107 – 109 ], Csde1 (Cold shock domain containing E1, RNA binding = UNR) [ 110 ], and Ifit3 (interferon-induced protein with tetratricopeptide repeats 3) [ 111 , 112 ].…”

Section: Resultsmentioning

confidence: 99%

Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation

Torres-Odio¹,

Key²,

Hoepken³

et al. 2017

J Neuroinflammation

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BackgroundPINK1 deficiency causes the autosomal recessive PARK6 variant of Parkinson’s disease. PINK1 activates ubiquitin by phosphorylation and cooperates with the downstream ubiquitin ligase PARKIN, to exert quality control and control autophagic degradation of mitochondria and of misfolded proteins in all cell types.MethodsGlobal transcriptome profiling of mouse brain and neuron cultures were assessed in protein-protein interaction diagrams and by pathway enrichment algorithms. Validation by quantitative reverse transcriptase polymerase chain reaction and immunoblots was performed, including human neuroblastoma cells and patient primary skin fibroblasts.ResultsIn a first approach, we documented Pink1-deleted mice across the lifespan regarding brain mRNAs. The expression changes were always subtle, consistently affecting “intracellular membrane-bounded organelles”. Significant anomalies involved about 250 factors at age 6 weeks, 1300 at 6 months, and more than 3500 at age 18 months in the cerebellar tissue, including Srsf10, Ube3a, Mapk8, Creb3, and Nfkbia. Initially, mildly significant pathway enrichment for the spliceosome was apparent. Later, highly significant networks of ubiquitin-mediated proteolysis and endoplasmic reticulum protein processing occurred. Finally, an enrichment of neuroinflammation factors appeared, together with profiles of bacterial invasion and MAPK signaling changes—while mitophagy had minor significance. Immunohistochemistry showed pronounced cellular response of Iba1-positive microglia and GFAP-positive astrocytes; brain lipidomics observed increases of ceramides as neuroinflammatory signs at old age.In a second approach, we assessed PINK1 deficiency in the presence of a stressor. Marked dysregulations of microbial defense factors Ifit3 and Rsad2 were consistently observed upon five analyses: (1) Pink1 −/− primary neurons in the first weeks after brain dissociation, (2) aged Pink1 −/− midbrain with transgenic A53T-alpha-synuclein overexpression, (3) human neuroblastoma cells with PINK1-knockdown and murine Pink1 −/− embryonal fibroblasts undergoing acute starvation, (4) triggering mitophagy in these cells with trifluoromethoxy carbonylcyanide phenylhydrazone (FCCP), and (5) subjecting them to pathogenic RNA-analogue poly(I:C). The stress regulation of MAVS, RSAD2, DDX58, IFIT3, IFIT1, and LRRK2 was PINK1 dependent. Dysregulation of some innate immunity genes was also found in skin fibroblast cells from PARK6 patients.ConclusionsThus, an individual biomarker with expression correlating to progression was not identified. Instead, more advanced disease stages involved additional pathways. Hence, our results identify PINK1 deficiency as an early modulator of innate immunity in neurons, which precedes late stages of neuroinflammation during alpha-synuclein spreading.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0928-0) contains supplementary material, which is available to authorized users.

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“…These findings suggest that the pro-restitution effects of Ac2-26 are not likely mediated by FPR2 and FPR3. To confirm the inhibitory effects of WRW4 on FPR2 and FPR3 in IECs, we incubated cells with selective FPR2 and FPR3 agonists, MMK1 (29) and F2L (30,31), respectively, and examined their influence on wound closure. As shown in Supplemental Figure 1, WRW4 inhibited the effects of MMK1 and F2L on wound closure.…”

Section: Introductionmentioning

confidence: 99%

Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair

et al. 2012

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N-formyl peptide receptors (FPRs) are critical regulators of host defense in phagocytes and are also expressed in epithelia. FPR signaling and function have been extensively studied in phagocytes, yet their functional biology in epithelia is poorly understood. We describe a novel intestinal epithelial FPR signaling pathway that is activated by an endogenous FPR ligand, annexin A1 (ANXA1), and its cleavage product Ac2-26, which mediate activation of ROS by an epithelial NADPH oxidase, NOX1. We show that epithelial cell migration was regulated by this signaling cascade through oxidative inactivation of the regulatory phosphatases PTEN and PTP-PEST, with consequent activation of focal adhesion kinase (FAK) and paxillin. In vivo studies using intestinal epithelial specific Nox1 -/-IEC and AnxA1 -/-mice demonstrated defects in intestinal mucosal wound repair, while systemic administration of ANXA1 promoted wound recovery in a NOX1-dependent fashion. Additionally, increased ANXA1 expression was observed in the intestinal epithelium and infiltrating leukocytes in the mucosa of ulcerative colitis patients compared with normal intestinal mucosa. Our findings delineate a novel epithelial FPR1/NOX1-dependent redox signaling pathway that promotes mucosal wound repair.

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Processing of HEBP1 by Cathepsin D Gives Rise to F2L, the Agonist of Formyl Peptide Receptor 3

Cited by 22 publications

References 57 publications

The formyl peptide receptor 1 exerts a tumor suppressor function in human gastric cancer by inhibiting angiogenesis

The formyl peptide receptor 1 exerts a tumor suppressor function in human gastric cancer by inhibiting angiogenesis

Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation

Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair

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