Article
- The EMBO Journal (2005) 24, 4368 - 4380
- doi:10.1038/sj.emboj.7600903
Published online: 15 December 2005
Subject Categories:
XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands
Ann-Hwee Lee1,a, Gerald C Chu2,a, Neal N Iwakoshi1 and Laurie H Glimcher1,3
- Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
Correspondence to:
Laurie H Glimcher, Department of Immunology and Infectious Diseases, Harvard School of Public Health, 651 Huntington Avenue, Building FXB, Room 205, Boston, MA 02115, USA. Tel.: +1 617 432 0622; Fax: +1 617 432 0084; E-mail: lglimche@hsph.harvard.edu
aThese authors contributed equally to this work
Received 9 September 2005; Accepted 14 November 2005
Abstract
The secretory function of cells relies on the capacity of the endoplasmic reticulum (ER) to fold and modify nascent polypeptides and to synthesize phospholipids for the subsequent trafficking of secretory proteins through the ER–Golgi network. We have previously demonstrated that the transcription factor XBP-1 activates the expression of certain ER chaperone genes and initiates ER biogenesis. Here, we have rescued the embryonic lethality of XBP-1 deficient fetuses by targeting an XBP-1 transgene selectively to hepatocytes (XBP-1-/-;LivXBP1). XBP-1-/-;LivXBP1 mice displayed abnormalities exclusively in secretory organs such as exocrine pancreas and salivary gland that led to early postnatal lethality from impaired production of pancreatic digestive enzymes. The ER was poorly developed in pancreatic and salivary gland acinar cells, accompanied by decreased expression of ER chaperone genes. Marked apoptosis of pancreatic acinar cells was observed during embryogenesis. Thus, the absence of XBP-1 results in an imbalance between the cargo load on the ER and its capacity to handle it, leading to the activation of ER stress-mediated proapoptotic pathways. These data lead us to propose that XBP-1 is both necessary and sufficient for the full biogenesis of the secretory machinery in exocrine cells.
Keywords:
- apoptosis,
- endoplasmic reticulum,
- exocrine pancreas,
- XBP-1,
- unfolded protein response
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