The IRE1alpha-XBP1 pathway of the unfolded protein response is required for adipogenesis.
Signaling cascades during adipogenesis culminate in the expression of two essential adipogenic factors, PPARgamma and C/EBPalpha. Here we demonstrate that the IRE1alpha-XBP1 pathway, the most conserved branch of the unfolded protein response (UPR), is indispensable for adipogenesis. Indeed, XBP1-deficient mouse embryonic fibroblasts and 3T3-L1 cells with XBP1 or IRE1alpha knockdown exhibit profound defects in adipogenesis. Intriguingly, C/EBPbeta, a key early adipogenic factor, induces Xbp1 expression by directly binding to its proximal promoter region. Subsequently, XBP1 binds to the promoter of Cebpa and activates its gene expression. The posttranscriptional splicing of Xbp1 mRNA by IRE1alpha is required as only the spliced form of XBP1 (XBP1s) rescues the adipogenic defect exhibited by XBP1-deficient cells. Taken together, our data show that the IRE1alpha-XBP1 pathway plays a key role in adipocyte differentiation by acting as a critical regulator of the morphological and functional transformations during adipogenesis.
Sha
Haibo
H
Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
He
Yin
Y
Chen
Hui
H
Wang
Cindy
C
Zenno
Anna
A
Shi
Hang
H
Yang
Xiaoyong
X
Zhang
Xinmin
X
Qi
Ling
L
D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D017510:Protein Folding; D020033:Protein Isoforms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071717:X-Box Binding Protein 1
D022782:CCAAT-Enhancer-Binding Protein-beta; D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases