Abstract
Accumulation of misfolded proteins in the endoplasmic reticulum (ER) induces the unfolded protein response (UPR), which alleviates protein overload in the secretory pathway. Although the UPR is activated under diverse pathological conditions, its physiological role during development and in adulthood has not been fully elucidated. Binding immunoglobulin protein (BiP) is an ER chaperone, which is central to ER function. We produced knock-in mice expressing a mutant BiP lacking the retrieval sequence to cause a defect in ER function without completely eliminating BiP. In embryonic fibroblasts, the UPR compensated for mutation of BiP. However, neonates expressing mutant BiP suffered respiratory failure due to impaired secretion of pulmonary surfactant by alveolar type II epithelial cells. Expression of surfactant protein (SP)-C was reduced and the lamellar body was malformed, indicating that BiP plays a critical role in the biosynthesis of pulmonary surfactant. Because pulmonary surfactant requires extensive post-translational processing in the secretory pathway, these findings suggest that in secretory cells, such as alveolar type II cells, the UPR is essential for managing the normal physiological ER protein overload that occurs during development. Moreover, failure of this adaptive mechanism may increase pulmonary susceptibility to environmental insults, such as hypoxia and ischemia, ultimately leading to neonatal respiratory failure.
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Abbreviations
- BiP:
-
binding immunoglobulin protein
- ER:
-
endoplasmic reticulum
- ERAD:
-
ER-associated protein degradation
- MEF:
-
mouse embryonic fibroblast
- PAS:
-
periodic acid Schiff
- SP:
-
surfactant protein
- UPR:
-
unfolded protein response
References
Ellgaard L, Helenius A . Quality control in the endoplasmic reticulum. Nat Rev Mol Cell Biol 2003; 4: 181–191.
Patil C, Walter P . Intracellular signaling from the endoplasmic reticulum to the nucleus: the unfolded protein response in yeast and mammals. Curr Opin Cell Biol 2001; 13: 349–355.
Schroder M, Kaufman RJ . The Mammalian unfolded protein response. Annu Rev Biochem 2005; 74: 739–789.
Kopito RR, Ron D . Conformational disease. Nat Cell Biol 2000; 2: E207–E209.
Kaufman RJ . Orchestrating the unfolded protein response in health and disease. J Clin Invest 2002; 110: 1389–1398.
Hamada H, Suzuki M, Yuasa S, Mimura N, Shinozuka N, Takada Y et al. Dilated cardiomyopathy caused by aberrant endoplasmic reticulum quality control in mutant KDEL receptor transgenic mice. Mol Cell Biol 2004; 24: 8007–8017.
Oyadomari S, Koizumi A, Takeda K, Gotoh T, Akira S, Araki E et al. Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J Clin Invest 2002; 109: 525–532.
Clark H, Clark LS . The genetics of neonatal respiratory disease. Semin Fetal Neonatal Med 2005; 10: 271–282.
Korimilli A, Gonzales LW, Guttentag SH . Intracellular localization of processing events in human surfactant protein B biosynthesis. J Biol Chem 2000; 275: 8672–8679.
Mulugeta S, Nguyen V, Russo SJ, Muniswamy M, Beers MF . A surfactant protein C precursor protein BRICHOS domain mutation causes endoplasmic reticulum stress, proteasome dysfunction, and caspase 3 activation. Am J Respir Cell Mol Biol 2005; 32: 521–530.
Bridges JP, Xu Y, Na CL, Wong HR, Weaver TE . Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C. J Cell Biol 2006; 172: 395–407.
Beers MF, Mulugeta S . Surfactant protein C biosynthesis and its emerging role in conformational lung disease. Annu Rev Physiol 2005; 67: 663–696.
Hendershot LM . The ER function BiP is a master regulator of ER function. Mt Sinai J Med 2004; 71: 289–297.
Sonnichsen B, Fullekrug J, Nguyen Van P, Diekmann W, Robinson DG, Mieskes G . Retention and retrieval: both mechanisms cooperate to maintain calreticulin in the endoplasmic reticulum. J Cell Sci 1994; 107: 2705–2717.
Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D . Dynamic interaction of BiP and ER stress transducers in the unfolded- protein response. Nat Cell Biol 2000; 2: 326–332.
Hammond C, Helenius A . Quality control in the secretory pathway: retention of a misfolded viral membrane glycoprotein involves cycling between the ER, intermediate compartment, and Golgi apparatus. J Cell Biol 1994; 126: 41–52.
Yamamoto K, Fujii R, Toyofuku Y, Saito T, Koseki H, Hsu VW et al. The KDEL receptor mediates a retrieval mechanism that contributes to quality control at the endoplasmic reticulum. EMBO J 2001; 20: 3082–3091.
Munro S, Pelham HR . A C-terminal signal prevents secretion of luminal ER proteins. Cell 1987; 48: 899–907.
Lewis MJ, Pelham HR . A human homologue of the yeast HDEL receptor. Nature 1990; 348: 162–163.
Beh CT, Rose MD . Two redundant systems maintain levels of resident proteins within the yeast endoplasmic reticulum. Proc Natl Acad Sci USA 1995; 92: 9820–9823.
Luo S, Mao C, Lee B, Lee AS . GRP78/BiP is required for cell proliferation and protecting the inner cell mass from apoptosis during early mouse embryonic development. Mol Cell Biol 2006; 26: 5688–5697.
Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 1998; 12: 982–995.
Taxis C, Vogel F, Wolf DH . ER-golgi traffic is a prerequisite for efficient ER degradation. Mol Biol Cell 2002; 13: 1806–1818.
Hallman M . Lung surfactant, respiratory failure, and genes. N Engl J Med 2004; 350: 1278–1280.
Nogee LM, de Mello DE, Dehner LP, Colten HR . Brief report: deficiency of pulmonary surfactant protein B in congenital alveolar proteinosis. N Engl J Med 1993; 328: 406–410.
Clark JC, Wert SE, Bachurski CJ, Stahlman MT, Stripp BR, Weaver TE et al. Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice. Proc Natl Acad Sci USA 1995; 92: 7794–7798.
Lahti M, Marttila R, Hallman M . Surfactant protein C gene variation in the Finnish population – association with perinatal respiratory disease. Eur J Hum Genet 2004; 12: 312–320.
Danlois F, Zaltash S, Johansson J, Robertson B, Haagsman HP, van Eijk M et al. Very low surfactant protein C contents in newborn Belgian White and Blue calves with respiratory distress syndrome. Biochem J 2000; 351 (Part 3): 779–787.
Kim SH, Creemers JW, Chu S, Thinakaran G, Sisodia SS . Proteolytic processing of familial British dementia-associated BRI variants: evidence for enhanced intracellular accumulation of amyloidogenic peptides. J Biol Chem 2002; 277: 1872–1877.
Nagai N, Hosokawa M, Itohara S, Adachi E, Matsushita T, Hosokawa N et al. Embryonic lethality of molecular chaperone hsp47 knockout mice is associated with defects in collagen biosynthesis. J Cell Biol 2000; 150: 1499–1506.
Mesaeli N, Nakamura K, Zvaritch E, Dickie P, Dziak E, Krause KH et al. Calreticulin is essential for cardiac development. J Cell Biol 1999; 144: 857–868.
Denzel A, Molinari M, Trigueros C, Martin JE, Velmurgan S, Brown S et al. Early postnatal death and motor disorders in mice congenitally deficient in calnexin expression. Mol Cell Biol 2002; 22: 7398–7404.
Zhang K, Shen X, Wu J, Sakaki K, Saunders T, Rutkowski DT . Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell 2006; 124: 587–599.
Wu J, Kaufman RJ . From acute ER stress to physiological roles of the unfolded protein response. Cell Death Differ 2006; 13: 374–384.
Scheuner D, Song B, McEwen E, Liu C, Laybutt R, Gillespie P . Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol Cell 2001; 7: 1165–1176.
Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM . Plasma cell differentiation requires the transcription factor XBP-1. Nature 2001; 412: 300–307.
Reimold AM, Etkin A, Clauss I, Perkins A, Friend DS, Zhang J . An essential role in liver development for transcription factor XBP-1. Genes Dev 2000; 14: 152–157.
Haas IG . and Meo T cDNA cloning of the immunoglobulin heavy chain binding protein. Proc Natl Acad Sci USA 1988; 85: 2250–2254.
Nagy A, Rossant J, Nagy R, Abramow-Newerly W, Roder JC . Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc Natl Acad Sci USA 1993; 90: 8424–8428.
Wilkinson DG, Nieto MA . Detection of messenger RNA by in situ hybridization to tissue sections and whole mounts. Methods Enzymol 1993; 225: 361–373.
Acknowledgements
We thank Dr. T Nishino for critical comments. We also thank R Kimura and R Fujii for excellent technical assistance. This work was supported by Grants-in-Aid for Science Research from the Ministry of Education, Culture, Sports, Science and Technology to TA.
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Mimura, N., Hamada, H., Kashio, M. et al. Aberrant quality control in the endoplasmic reticulum impairs the biosynthesis of pulmonary surfactant in mice expressing mutant BiP. Cell Death Differ 14, 1475–1485 (2007). https://doi.org/10.1038/sj.cdd.4402151
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DOI: https://doi.org/10.1038/sj.cdd.4402151
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