Emerging roles for XBP1, a sUPeR transcription factor

Abstract

X-box binding protein 1 (XBP1) is a unique basic region leucine zipper (bZIP) transcription factor whose active form is generated by a nonconventional splicing reaction upon disruption of homeostasis in the endoplasmic reticulum (ER) and activation of the unfolded protein response (UPR). XBP1, first identified as a key regulator of major histocompatibility complex (MHC) class II gene expression in B cells, represents the most conserved signaling component of UPR and is critical for cell fate determination in response to ER stress. Here we review recent advances in our understanding of this multifaceted transcription factor in health and diseases.

Figure 1

Three major UPR pathways in metazoans. Misfolded proteins or homeostatic alterations in the ER activate three ER-resident sensors: IRE1α, PERK, and ATF6. Key players in each pathway are highlighted. Among the three branches, the IRE1α–XBP1 pathway, the focus of this review, is the most evolutionarily conserved. IRE1α mediates Xbp1u mRNA splicing to generate a potent transcription factor XBP1s (the spliced form of XBP1). XBP1s regulates a diverse array of genes involved in ER homeostasis, adipogenesis, lipogenesis, and cell survival. In addition, activation of IRE1α may lead to phosphorylation of JNK and hence influence the outcome of inflammatory response.

Figure 2

Comparison of XBP1u and XBP1s proteins. (A) The domain comparison of XBP1u and XBP1s proteins. Number refers to amino acid position of mouse proteins. DBD, DNA binding domain; TAD, transactivation domain. (B) Western blot of XBP1 in nuclear extract of mouse pancreatic lysates. Note the positions of endogenous XBP1u and XBP1s proteins. (C) Western blot of XBP1s in nuclear extract of mouse macrophage RAW 264.7 cells treated with 300 nM thapsigargin (Tg) for 2 h. Cells were stably expressing either XBP1 RNAi or control RNAi. Lamin, a loading control. (D) Sequence alignment of XBP1s from different species. DBD, underlined; SUMOylation lysine (K) sites, K276 and K297; XBP1s unique sequence, arrow.

Figure 3

XBP1 in B cell differentiation to plasma cells. LPS and IL-4 stimulate the expression of Xbp1 mRNA and lead to the elevation of XBP1s protein in activated B cells (A). XBP1s is responsible for expanding the ER capacity in preparation for upcoming waves of immunoglobulin (Ig) biosynthesis in preplasmablasts (B). In fully differentiated plasma cells, ER capacity reaches a new set point of homeostasis to accommodate Ig biosynthesis (C). The question of whether and when UPR activation occurs during this process remains open.

Figure 4

Simplified schematic outline of IRE1α–XBP1-mediated signaling cascades during B cell differentiation, adipogenesis, and myogenesis. The key transcription factors (regulators) that are responsible for Xbp1 mRNA induction, XBP1s targets, and physiological effects of the signaling cascades are shown for each event.