Bettigole Sarah E, Lis Raphael, Adoro Stanley, Lee Ann-Hwee, Spencer Lisa A, Weller Peter F, Glimcher Laurie H
1] Program in Immunology, Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA. [3] Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, New York, USA.
1] Ansary Stem Cell Institute, Department of Genetic Medicine, and Howard Hughes Medical Institute, Weill Cornell Medical College, New York, New York, USA. [2] Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College, New York, New York, USA.
Nat Immunol. 2015 Aug;16(8):829-37. doi: 10.1038/ni.3225. Epub 2015 Jul 6.
The transcription factor XBP1 has been linked to the development of highly secretory tissues such as plasma cells and Paneth cells, yet its function in granulocyte maturation has remained unknown. Here we discovered an unexpectedly selective and absolute requirement for XBP1 in eosinophil differentiation without an effect on the survival of basophils or neutrophils. Progenitors of myeloid cells and eosinophils selectively activated the endoribonuclease IRE1α and spliced Xbp1 mRNA without inducing parallel endoplasmic reticulum (ER) stress signaling pathways. Without XBP1, nascent eosinophils exhibited massive defects in the post-translational maturation of key granule proteins required for survival, and these unresolvable structural defects fed back to suppress critical aspects of the transcriptional developmental program. Hence, we present evidence that granulocyte subsets can be distinguished by their differential reliance on secretory-pathway homeostasis.
转录因子XBP1与浆细胞和潘氏细胞等高分泌组织的发育有关，但其在粒细胞成熟中的功能仍不清楚。在此，我们发现嗜酸性粒细胞分化对XBP1有出人意料的选择性和绝对需求，而对嗜碱性粒细胞或中性粒细胞的存活没有影响。髓样细胞和嗜酸性粒细胞的祖细胞选择性激活核糖核酸内切酶IRE1α并剪接Xbp1 mRNA，而不诱导平行的内质网（ER）应激信号通路。没有XBP1，新生嗜酸性粒细胞在生存所需的关键颗粒蛋白的翻译后成熟过程中表现出大量缺陷，这些无法解决的结构缺陷会反馈抑制转录发育程序的关键方面。因此，我们提供的证据表明，粒细胞亚群可因其对分泌途径稳态的不同依赖而加以区分。
