Truyền tín hiệu trong các rối loạn chuyển hóa di truyền: một mô hình cho một cơ chế gây bệnh có thể xảy ra

Journal of Inherited Metabolic Disease - Tập 38 - Trang 729-740 - 2015
Avihu Boneh1,2
1Metabolic Research, Murdoch Childrens Research Institute, Royal Children’s Hospital, Melbourne, Australia
2Department of Paediatrics, University of Melbourne, Melbourne, Australia

Tóm tắt

Truyền tín hiệu là quá trình mà các tín hiệu bên ngoài hoặc bên trong tác động đến các hiệu ứng sinh học nội bào và điều chỉnh giao tiếp nội bào. Một thành phần quan trọng của con đường truyền tín hiệu là chất thông báo thứ hai, được sản xuất khi tế bào bị kích thích và làm trung gian các hiệu ứng của nó qua quá trình phosphory hóa và dephosphory hóa các protein đích. Sự tích tụ hoặc thiếu hụt nội bào của các chất chuyển hóa hoạt động như các chất thông báo thứ hai, do lỗi bẩm sinh của quá trình trao đổi chất, có thể dẫn đến sự rối loạn của các con đường truyền tín hiệu và sự gián đoạn của sự cân bằng giữa chúng, tạo thành liên kết thiếu giữa kiểu gen, kiểu hình sinh hóa và kiểu hình lâm sàng. Các chất thông báo thứ hai chính mà có liên quan giả thuyết đến sinh bệnh học của các rối loạn chuyển hóa di truyền là ‘lipid sinh học’ (lipid phức tạp và axit béo chuỗi dài), ‘canxi’, ‘stress’ (các yếu tố thẩm thấu, oxy/nitơ phản ứng, protein bị gấp nếp sai và các yếu tố khác) và ‘chuyển hóa’ (tỷ lệ AMP/ATP, leucine, glutamine). Chúng hoạt động thông qua protein kinase C, các kinase phụ thuộc canxi (CamK) và phosphatase (CN), các kinase ‘được điều chỉnh bởi stress’ (MAPK) và kinase phụ thuộc vào AMP/ATP (AMPK). Những con đường truyền tín hiệu này dẫn đến sự tăng sinh tế bào, phản ứng viêm, tự thực (và mitophagy) và apoptosis, cho thấy chỉ có một vài con đường cuối cùng chung liên quan đến cơ chế gây bệnh này. Vẫn còn nhiều câu hỏi về sự phức tạp của các tác động của các chất chuyển hóa tích tụ lên các con đường truyền tín hiệu khác nhau, và về vai trò tương đối và nguồn gốc của các chất thông báo thứ hai ‘proxy’ như các loại oxy phản ứng. Một hiểu biết tốt hơn về các con đường truyền tín hiệu trong các rối loạn chuyển hóa di truyền có thể tăng cường sự phát triển của các liệu pháp mới trong những trường hợp mà việc bình thường hóa nồng độ nội bào của chất thông báo thứ hai là không thể hoặc không thực tế.

Từ khóa

#truyền tín hiệu #rối loạn chuyển hóa di truyền #chất thông báo thứ hai #sinh bệnh học #protein kinase #quá trình tăng sinh tế bào

Tài liệu tham khảo

Airola MV, Hannun YA (2013) Sphingolipid metabolism and neutral sphingomyelinases. Handb Exp Pharmacol :57-76 Aledo JC (2014) Life-history constraints on the mechanisms that control the rate of ROS production. Curr Genomics 15:217–230 Andreux PA, Houtkooper RH, Auwerx J (2013) Pharmacological approaches to restore mitochondrial function. Nat Rev Drug Discov 12:465–483 Bao XM, Wu CF, Lu GP (2010) Atorvastatin inhibits homocysteine-induced oxidative stress and apoptosis in endothelial progenitor cells involving Nox4 and p38MAPK. Atherosclerosis 210:114–121 Bastin J, Lopes-Costa A, Djouadi F (2011) Exposure to resveratrol triggers pharmacological correction of fatty acid utilization in human fatty acid oxidation-deficient fibroblasts. Hum Mol Genet 20:2048–2057 Ben-Yaacov A, Minichiello J, Newgreen D, Boneh A (2000) Perturbation of protein kinase C subtype activation in X-ALD fibroblasts: possible involvement of protein kinase C in the pathogenesis of adrenoleukodystrophy. J Inherit Metab Dis 23:416–420 Berridge MJ (1988) The Croonian lecture, 1988. Inositol lipids and calcium signalling. Proc R Soc Lond B Biol Sci 234:359–378 Berridge MJ (2014) Cell signalling Biology. Biochem J doi:10.1042/csb0001002 Bobermin LD, Quincozes-Santos A, Guerra MC et al (2012) Resveratrol prevents ammonia toxicity in astroglial cells. PLoS One 7:e52164 Bobermin LD, Souza DO, Goncalves CA, Quincozes-Santos A (2013) Lipoic acid protects C6 cells against ammonia exposure through Na(+)-K(+)-Cl(-) co-transporter and PKC pathway. Toxicol In Vitro 27:2041–2048 Boneh A (1995) Possible role for protein kinase C in the pathogenesis of inborn errors of metabolism. J Cell Biochem 59:27–32 Boneh A (2002) A model for PKC involvement in the pathogenesis of inborn errors of metabolism. Trends Mol Med 8:524–531 Brand MD (2010) The sites and topology of mitochondrial superoxide production. Exp Gerontol 45:466–472 Cabeza C, Figueroa A, Lazo OM et al (2012) Cholinergic abnormalities, endosomal alterations and up-regulation of nerve growth factor signaling in Niemann-Pick type C disease. Mol Neurodegener 7:11 Cargnello M, Roux PP (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev 75:50–83 Chalfant CE, Spiegel S (2005) Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. J Cell Sci 118:4605–4612 Chaudhari N, Talwar P, Parimisetty A, Lefebvre d’Hellencourt C, Ravanan P (2014) A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress. Front Cell Neurosci 8:213 Cohen P (2002) The origins of protein phosphorylation. Nat Cell Biol 4:E127–E130 Cornelius N, Corydon TJ, Gregersen N, Olsen RK (2014) Cellular consequences of oxidative stress in riboflavin responsive multiple acyl-CoA dehydrogenation deficiency patient fibroblasts. Hum Mol Genet 23:4285–4301 Csaki LS, Dwyer JR, Fong LG, Tontonoz P, Young SG, Reue K (2013) Lipins, lipinopathies, and the modulation of cellular lipid storage and signaling. Prog Lipid Res 52:305–316 Cuvillier O, Pirianov G, Kleuser B et al (1996) Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 381:800–803 Dall’Armi C, Devereaux KA, Di Paolo G (2013) The role of lipids in the control of autophagy. Curr Biol 23:R33–R45 East DA, Campanella M (2013) Ca2+ in quality control: an unresolved riddle critical to autophagy and mitophagy. Autophagy 9:1710–1719 Faergeman NJ, Knudsen J (1997) Role of long-chain fatty acyl-CoA esters in the regulation of metabolism and in cell signalling. Biochem J 323(Pt 1):1–12 Galea E, Launay N, Portero-Otin M et al (2012) Oxidative stress underlying axonal degeneration in adrenoleukodystrophy: a paradigm for multifactorial neurodegenerative diseases? Biochim Biophys Acta 1822:1475–1488 Gallego-Villar L, Perez-Cerda C, Perez B et al (2013) Functional characterization of novel genotypes and cellular oxidative stress studies in propionic acidemia. J Inherit Metab Dis 36:731–740 Gallinetti J, Harputlugil E, Mitchell JR (2013) Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR. Biochem J 449:1–10 Gangoiti P, Granado MH, Wang SW, Kong JY, Steinbrecher UP, Gomez-Munoz A (2008) Ceramide 1-phosphate stimulates macrophage proliferation through activation of the PI3-kinase/PKB, JNK and ERK1/2 pathways. Cell Signal 20:726–736 Giri S, Jatana M, Rattan R, Won JS, Singh I, Singh AK (2002) Galactosylsphingosine (psychosine)-induced expression of cytokine-mediated inducible nitric oxide synthases via AP-1 and C/EBP: implications for Krabbe disease. FASEB J 16:661–672 Griffiths EJ, Rutter GA (2009) Mitochondrial calcium as a key regulator of mitochondrial ATP production in mammalian cells. Biochim Biophys Acta 1787:1324–1333 Grkovich A, Dennis EA (2009) Phosphatidic acid phosphohydrolase in the regulation of inflammatory signaling. Adv Enzyme Regul 49:114–120 Han GS, Carman GM (2010) Characterization of the human LPIN1-encoded phosphatidate phosphatase isoforms. J Biol Chem 285:14628–14638 Hannun YA, Bell RM (1987) Lysosphingolipids inhibit protein kinase C: implications for the sphingolipidoses. Science 235:670–674 Hannun YA, Obeid LM (2008) Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol 9:139–150 Head BP, Patel HH, Insel PA (2014) Interaction of membrane/lipid rafts with the cytoskeleton: impact on signaling and function: membrane/lipid rafts, mediators of cytoskeletal arrangement and cell signaling. Biochim Biophys Acta 1838:532–545 Inoue M, Kishimoto A, Takai Y, Nishizuka Y (1977) Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. II. Proenzyme and its activation by calcium-dependent protease from rat brain. J Biol Chem 252:7610–7616 Jakóbkiewicz-Banecka J, Piotrowska E, Narajczyk M, Barańska S, Węgrzyn G (2009) Genistein-mediated inhibition of glycosaminoglycan synthesis, which corrects storage in cells of patients suffering from mucopolysaccharidoses, acts by influencing an epidermal growth factor-dependent pathway. J Biomed Sci 16:26 Jiang F, Zhang Y, Dusting GJ (2011) NADPH oxidase-mediated redox signaling: roles in cellular stress response, stress tolerance, and tissue repair. Pharmacol Rev 63:218–242 Johnson SC, Yanos ME, Kayser EB et al (2013) mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 342:1524–1528 Jorge-Finnigan A, Gamez A, Perez B, Ugarte M, Richard E (2010) Different altered pattern expression of genes related to apoptosis in isolated methylmalonic aciduria cblB type and combined with homocystinuria cblC type. Biochim Biophys Acta 1802:959–967 Kim EK, Choi EJ (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 1802:396–405 Kingma SD, Wagemans T, IJlst L, Wijburg FA, van Vlies N (2014) Genistein increases glycosaminoglycan levels in mucopolysaccharidosis type I cell models. J Inherit Metab Dis 37:813–821 Labilloy A, Youker RT, Bruns JR et al (2014) Altered dynamics of a lipid raft associated protein in a kidney model of Fabry disease. Mol Genet Metab 111:184–192 Lallena MJ, Diaz-Meco MT, Bren G, Paya CV, Moscat J (1999) Activation of IkappaB kinase beta by protein kinase C isoforms. Mol Cell Biol 19:2180–2188 Lamari F, Mochel F, Sedel F, Saudubray JM (2013) Disorders of phospholipids, sphingolipids and fatty acids biosynthesis: toward a new category of inherited metabolic diseases. J Inherit Metab Dis 36:411–425 Li J, Kim SG, Blenis J (2014a) Rapamycin: one drug, many effects. Cell Metab 19:373–379 Li J, Li J, Yue Y et al (2014b) Genistein suppresses tumor necrosis factor alpha-induced inflammation via modulating reactive oxygen species/Akt/nuclear factor kappaB and adenosine monophosphate-activated protein kinase signal pathways in human synoviocyte MH7A cells. Drug Des Devel Ther 8:315–323 Littman ED, Pitchumoni S, Garfinkel MR, Opara EC (2000) Role of protein kinase C isoenzymes in fatty acid stimulation of insulin secretion. Pancreas 20:256–263 Lopes Costa A, Le Bachelier C, Mathieu L et al (2014) Beneficial effects of resveratrol on respiratory chain defects in patients’ fibroblasts involve estrogen receptor and estrogen-related receptor alpha signaling. Hum Mol Genet 23:2106–2119 Moshal KS, Sen U, Tyagi N et al (2006) Regulation of homocysteine-induced MMP-9 by ERK1/2 pathway. Am J Physiol Cell Physiol 290:C883–C891 Moskot M, Montefusco S, Jakobkiewicz-Banecka J et al (2014) The phytoestrogen genistein modulates lysosomal metabolism and transcription factor EB (TFEB) activation. J Biol Chem 289:17054–17069 Naon D, Scorrano L (2014) At the right distance: ER-mitochondria juxtaposition in cell life and death. Biochim Biophys Acta 1843:2184–2194 Nesher M, Boneh A (1994) Effect of fatty acids and their acyl-CoA esters on protein kinase C activity in fibroblasts: possible implications in fatty acid oxidation defects. Biochim Biophys Acta 1221:66–72 Nishizuka Y (2001) The protein kinase C family and lipid mediators for transmembrane signaling and cell regulation. Alcohol Clin Exp Res 25:3S–7S Nishizuka Y (2003) Discovery and prospect of protein kinase C research: epilogue. J Biochem 133:155–158 Olsen RK, Cornelius N, Gregersen N (2013) Genetic and cellular modifiers of oxidative stress: what can we learn from fatty acid oxidation defects? Mol Genet Metab 110(Suppl):S31–S39 Pahan K, Khan M, Singh I (1998) Therapy for X-adrenoleukodystrophy: normalization of very long chain fatty acids and inhibition of induction of cytokines by cAMP. J Lipid Res 39:1091–1100 Pani B, Singh BB (2009) Lipid rafts/caveolae as microdomains of calcium signaling. Cell Calcium 45:625–633 Pany S, Majhi A, Das J (2012) PKC activation by resveratrol derivatives with unsaturated aliphatic chain. PLoS One 7:e52888 Patel HH, Insel PA (2009) Lipid rafts and caveolae and their role in compartmentation of redox signaling. Antioxid Redox Signal 11:1357–1372 Pessoa-Pureur R, Wajner M (2007) Cytoskeleton as a potential target in the neuropathology of maple syrup urine disease: insight from animal studies. J Inherit Metab Dis 30:664–672 Peterson TR, Sengupta SS, Harris TE et al (2011) mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146:408–420 Richard E, Desviat LR, Ugarte M, Perez B (2013) Oxidative stress and apoptosis in homocystinuria patients with genetic remethylation defects. J Cell Biochem 114:183–191 Rodriguez-Lafrasse C, Rousson R, Valla S, Antignac P, Louisot P, Vanier MT (1997) Modulation of protein kinase C by endogenous sphingosine: inhibition of phorbol dibutyrate binding in Niemann-Pick C fibroblasts. Biochem J 325(Pt 3):787–791 Rosse C, Linch M, Kermorgant S, Cameron AJ, Boeckeler K, Parker PJ (2010) PKC and the control of localized signal dynamics. Nat Rev Mol Cell Biol 11:103–112 Saez PJ, Orellana JA, Vega-Riveros N et al (2013) Disruption in connexin-based communication is associated with intracellular Ca(2)(+) signal alterations in astrocytes from Niemann-Pick type C mice. PLoS One 8:e71361 Schluter A, Espinosa L, Fourcade S et al (2012) Functional genomic analysis unravels a metabolic-inflammatory interplay in adrenoleukodystrophy. Hum Mol Genet 21:1062–1077 Schrader M, Fahimi HD (2006) Peroxisomes and oxidative stress. Biochim Biophys Acta 1763:1755–1766 Signorello MG, Segantin A, Passalacqua M, Leoncini G (2009) Homocysteine decreases platelet NO level via protein kinase C activation. Nitric Oxide 20:104–113 Takai Y, Kishimoto A, Inoue M, Nishizuka Y (1977) Studies on a cyclic nucleotide-independent protein kinase and its proenzyme in mammalian tissues. I. Purification and characterization of an active enzyme from bovine cerebellum. J Biol Chem 252:7603–7609 Towler MC, Hardie DG (2007) AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res 100:328–341 Wang G, Siow YL, O K (2000) Homocysteine stimulates nuclear factor kappaB activity and monocyte chemoattractant protein-1 expression in vascular smooth-muscle cells: a possible role for protein kinase C. Biochem J 352(Pt 3):817–826 White AB, Givogri MI, Lopez-Rosas A et al (2009) Psychosine accumulates in membrane microdomains in the brain of krabbe patients, disrupting the raft architecture. J Neurosci 29:6068–6077 Wilkins BJ, Dai YS, Bueno OF et al (2004) Calcineurin/NFAT coupling participates in pathological, but not physiological, cardiac hypertrophy. Circ Res 94:110–118 Winter JN, Fox TE, Kester M, Jefferson LS, Kimball SR (2010) Phosphatidic acid mediates activation of mTORC1 through the ERK signaling pathway. Am J Physiol Cell Physiol 299:C335–C344 Yan GR, Xiao CL, He GW et al (2010a) Global phosphoproteomic effects of natural tyrosine kinase inhibitor, genistein, on signaling pathways. Proteomics 10:976–986 Yan TT, Li Q, Zhang XH et al (2010b) Homocysteine impaired endothelial function through compromised vascular endothelial growth factor/Akt/endothelial nitric oxide synthase signalling. Clin Exp Pharmacol Physiol 37:1071–1077 Zeidan YH, Hannun YA (2007) Translational aspects of sphingolipid metabolism. Trends Mol Med 13:327–336 Zhang H, Desai NN, Olivera A, Seki T, Brooker G, Spiegel S (1991) Sphingosine-1-phosphate, a novel lipid, involved in cellular proliferation. J Cell Biol 114:155–167 Zhang D, Liu ZX, Choi CS et al (2007) Mitochondrial dysfunction due to long-chain Acyl-CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Proc Natl Acad Sci U S A 104:17075–17080 Zong H, Ren JM, Young LH et al (2002) AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci U S A 99:15983–15987 Zou CG, Banerjee R (2005) Homocysteine and redox signaling. Antioxid Redox Signal 7:547–559