Activation of Endoplasmic Reticulum Stress and Unfolded Protein Response in Congenital Factor VII Deficiency

Abstract

Congenital factor (F) VII deficiency is a bleeding disorder caused by a heterogeneous pattern of mutations in the F7 gene. Protein misfolding due to mutations is a strong candidate mechanism to produce the highly represented type I FVII deficiency forms, characterized by a concomitant deficiency of FVII antigen and activity. Misfolded proteins can accumulate within the endoplasmic reticulum (ER) causing ER stress with subsequent activation of the unfolded protein response (UPR). So far, there are limited data on this important issue in FVII deficiency. In this study, we chose as candidate FVII model mutations, the p.Q160R, p.I289del and p.A354V-p.P464Hfs, which are all associated with severe to moderate type I FVII deficiency. In vitro expression of the recombinant (r) mutants rFVII-160R, rFVII-289del or rFVII-354V-464Hfs, which are characterized by either amino acid substitution, deletion, or by an extended carboxyl terminus, demonstrated inefficient secretion of the mutant proteins, probably caused by intracellular retention and association with ER chaperones. Both ER stress and UPR were activated following expression of all FVII mutants, with the highest response for rFVII-289del and rFVII-354V-464Hfs. These data unravel new knowledge on pathogenic mechanisms leading to FVII deficiency, and support the investigation of pharmaceutical modulators of ER stress and UPR as therapeutic agents.

Keywords

factor VII deficiency - endoplasmic reticulum stress - unfolded protein response

• References

• 1 Hagen FS, Gray CL, O'Hara P. , et al. Characterization of a cDNA coding for human factor VII. Proc Natl Acad Sci U S A 1986; 83 (08) 2412-2416
• 2 McVey JH, Boswell E, Mumford AD, Kemball-Cook G, Tuddenham EG. Factor VII deficiency and the FVII mutation database. Hum Mutat 2001; 17 (01) 3-17
• 3 Rao LV, Rapaport SI. Activation of factor VII bound to tissue factor: a key early step in the tissue factor pathway of blood coagulation. Proc Natl Acad Sci U S A 1988; 85 (18) 6687-6691
• 4 Mackman N. The role of tissue factor and factor VIIa in hemostasis. Anesth Analg 2009; 108 (05) 1447-1452
• 5 Girolami A, Bertozzi I, de Marinis GB, Bonamigo E, Fabris F. Activated FVII levels in factor VII Padua (Arg304Gln) coagulation disorder and in true factor VII deficiency: a study in homozygotes and heterozygotes. Hematology 2011; 16 (05) 308-312
• 6 Valastyan JS, Lindquist S. Mechanisms of protein-folding diseases at a glance. Dis Model Mech 2014; 7 (01) 9-14
• 7 Kavlie A, Orning L, Grindflek A, Stormorken H, Prydz H. Characterization of a factor VII molecule carrying a mutation in the second epidermal growth factor-like domain. Thromb Haemost 1998; 79 (06) 1136-1143
• 8 Branchini A, Baroni M, Pfeiffer C. , et al. Coagulation factor VII variants resistant to inhibitory antibodies. Thromb Haemost 2014; 112 (05) 972-980
• 9 Mariani G, Herrmann FH, Dolce A. , et al; International Factor VII Deficiency Study Group. Clinical phenotypes and factor VII genotype in congenital factor VII deficiency. Thromb Haemost 2005; 93 (03) 481-487
• 10 Ma Y, Hendershot LM. The mammalian endoplasmic reticulum as a sensor for cellular stress. Cell Stress Chaperones 2002; 7 (02) 222-229
• 11 Yoshida H. ER stress and diseases. FEBS J 2007; 274 (03) 630-658
• 12 Malhotra JD, Miao H, Zhang K. , et al. Antioxidants reduce endoplasmic reticulum stress and improve protein secretion. Proc Natl Acad Sci U S A 2008; 105 (47) 18525-18530
• 13 Tjeldhorn L, Iversen N, Sandvig K, Bergan J, Sandset PM, Skretting G. Protein C mutation (A267T) results in ER retention and unfolded protein response activation. PLoS One 2011; 6 (08) e24009
• 14 Brown HC, Gangadharan B, Doering CB. Enhanced biosynthesis of coagulation factor VIII through diminished engagement of the unfolded protein response. J Biol Chem 2011; 286 (27) 24451-24457
• 15 Cronin KR, Mangan TP, Carew JA. Upregulation of the coagulation factor VII gene during glucose deprivation is mediated by activating transcription factor 4. PLoS One 2012; 7 (07) e40994
• 16 Pinotti M, Toso R, Redaelli R, Berrettini M, Marchetti G, Bernardi F. Molecular mechanisms of FVII deficiency: expression of mutations clustered in the IVS7 donor splice site of factor VII gene. Blood 1998; 92 (05) 1646-1651
• 17 Tjeldhorn L, Iversen N, Sandvig K, Bergan J, Sandset PM, Skretting G. Functional characterization of the protein C A267T mutation: evidence for impaired secretion due to defective intracellular transport. BMC Cell Biol 2010; 11: 67
• 18 Tanaka R, Nakashima D, Suzuki A. , et al. Impaired secretion of carboxyl-terminal truncated factor VII due to an F7 nonsense mutation associated with FVII deficiency. Thromb Res 2010; 125 (03) 262-266
• 19 Hunault M, Arbini AA, Carew JA, Peyvandi F, Bauer KA. Characterization of two naturally occurring mutations in the second epidermal growth factor-like domain of factor VII. Blood 1999; 93 (04) 1237-1244
• 20 Herrmann FH, Wulff K, Strey R, Siegemund A, Astermark J, Schulman S. ; International Greifswald Registry of FVII Deficiency. Variability of clinical manifestation of factor VII-deficiency in homozygous and heterozygous subjects of the European F7 gene mutation A294V. Haematologica 2008; 93 (08) 1273-1275
• 21 Toso R, Pinotti M, High KA, Pollak ES, Bernardi F. A frequent human coagulation Factor VII mutation (A294V, c152) in loop 140s affects the interaction with activators, tissue factor and substrates. Biochem J 2002; 363 (Pt 2): 411-416
• 22 Arbini AA, Bodkin D, Lopaciuk S, Bauer KA. Molecular analysis of Polish patients with factor VII deficiency. Blood 1994; 84 (07) 2214-2220
• 23 Rutkowski DT, Kaufman RJ. A trip to the ER: coping with stress. Trends Cell Biol 2004; 14 (01) 20-28
• 24 Sitia R, Braakman I. Quality control in the endoplasmic reticulum protein factory. Nature 2003; 426 (6968): 891-894
• 25 Iwawaki T, Hosoda A, Okuda T. , et al. Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress. Nat Cell Biol 2001; 3 (02) 158-164
• 26 Brostrom CO, Brostrom MA. Regulation of translational initiation during cellular responses to stress. Prog Nucleic Acid Res Mol Biol 1998; 58: 79-125
• 27 Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 2001; 107 (07) 881-891
• 28 Marzec M, Eletto D, Argon Y. GRP94: An HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum. Biochim Biophys Acta 2012; 1823: 774-787
• 29 Harding HP, Novoa I, Zhang Y. , et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 2000; 6 (05) 1099-1108
• 30 Ma Y, Hendershot LM. Delineation of a negative feedback regulatory loop that controls protein translation during endoplasmic reticulum stress. J Biol Chem 2003; 278 (37) 34864-34873
• 31 Ma Y, Brewer JW, Diehl JA, Hendershot LM. Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol 2002; 318 (05) 1351-1365
• 32 Kim I, Xu W, Reed JC. Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities. Nat Rev Drug Discov 2008; 7 (12) 1013-1030
• 33 Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 2012; 13 (02) 89-102
• 34 DuRose JB, Tam AB, Niwa M. Intrinsic capacities of molecular sensors of the unfolded protein response to sense alternate forms of endoplasmic reticulum stress. Mol Biol Cell 2006; 17 (07) 3095-3107
• 35 Rutkowski DT, Kaufman RJ. That which does not kill me makes me stronger: adapting to chronic ER stress. Trends Biochem Sci 2007; 32 (10) 469-476
• 36 Yoshida H, Haze K, Yanagi H, Yura T, Mori K. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins. Involvement of basic leucine zipper transcription factors. J Biol Chem 1998; 273 (50) 33741-33749
• 37 Lee AS. Mammalian stress response: induction of the glucose-regulated protein family. Curr Opin Cell Biol 1992; 4 (02) 267-273
• 38 Miao HZ, Sirachainan N, Palmer L. , et al. Bioengineering of coagulation factor VIII for improved secretion. Blood 2004; 103 (09) 3412-3419
• 39 Hetz C, Chevet E, Harding HP. Targeting the unfolded protein response in disease. Nat Rev Drug Discov 2013; 12 (09) 703-719
• 40 Kraskiewicz H, FitzGerald U. InterfERing with endoplasmic reticulum stress. Trends Pharmacol Sci 2012; 33 (02) 53-63
• 41 Colla E, Coune P, Liu Y. , et al. Endoplasmic reticulum stress is important for the manifestations of α-synucleinopathy in vivo. J Neurosci 2012; 32 (10) 3306-3320
• 42 United States Food and Drug Administration. Hematology/Oncology (Cancer) Approvals & Safety Notifications. Available at: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm . Accessed February 15, 2018
• 43 Cortez L, Sim V. The therapeutic potential of chemical chaperones in protein folding diseases. Prion 2014; 8 (02) 8
• 44 Van Goor F, Hadida S, Grootenhuis PD. , et al. Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809. Proc Natl Acad Sci U S A 2011; 108 (46) 18843-18848
• 45 Arbini AA, Mannucci M, Bauer KA. A Thr359Met mutation in factor VII of a patient with a hereditary deficiency causes defective secretion of the molecule. Blood 1996; 87 (12) 5085-5094
• 46 Enjolras N, Plantier JL, Rodriguez MH. , et al. Two novel mutations in EGF-like domains of human factor IX dramatically impair intracellular processing and secretion. J Thromb Haemost 2004; 2 (07) 1143-1154
• 47 Katsumi A, Senda T, Yamashita Y. , et al. Protein C Nagoya, an elongated mutant of protein C, is retained within the endoplasmic reticulum and is associated with GRP78 and GRP94. Blood 1996; 87 (10) 4164-4175
• 48 Griesemer M, Young C, Robinson AS, Petzold L. BiP clustering facilitates protein folding in the endoplasmic reticulum. PLOS Comput Biol 2014; 10 (07) e1003675