MicroRNA-210 (miR-210) is a signature microRNA of hypoxia. We found robust increase (>100-fold) of miR-210 abundance in activated T cells, especially in the TH17 lineage. Hypoxia synergized with T cell receptor (TCR)–CD28 stimulation to accelerate and increase the magnitude of Mir210 expression. Mir210 was directly regulated by HIF-1α, a key regulator of TH17 polarization. Surprisingly, Hif1a was identified as a miR-210-target, suggesting negative-feedback by miR-210 to inhibit HIF-1α protein expression. Deletion of Mir210 promoted TH17 differentiation under conditions with limited oxygen. In experimental colitis, miR-210 reduced Hif1a transcript abundance, reduced the proportion of cells producing inflammatory cytokines and controlled disease severity. Our study identifies miR-210 as an important regulator of T cell differentiation in hypoxia, which can limit immunopathology.

MZB1 (pERp1) is a B-cell-specific and endoplasmic reticulum (ER)-localized protein implicated in antibody secretion and integrin-mediated cell adhesion. Here, we examine the role of MZB1 in vivo by conditional gene inactivation in the mouse germline and at different stages of B lymphopoiesis. Deletion of MZB1 impairs humoral immune responses and antibody secretion in plasma cells that naturally undergo ER stress. In addition, we found that experimental induction of ER stress by tunicamycin injections in mice results in a block of pro-B-cell to pre-B-cell differentiation specifically in Mzb1 -/-mice. A similar developmental block was observed in Mzb1 fl/fl mb1Cre mice, whereby a Cre recombinase-induced genotoxic stress unmasks a role for MZB1 in the surface expression of immunoglobulin m heavy chains (mHCs). MZB1 associates directly with the substrate-specific chaperone GRP94 (also called HSP90B1 or gp96) in an ATP-sensitive manner and is required for the interaction of GRP94 with mHCs upon ER stress. Thus, MZB1 seems to act as a substrate-specific cochaperone of GRP94 that enables proper biosynthesis of mHCs under conditions of ER stress.

Transcriptional regulation by the canonical Wnt pathway involves the stabilization and nuclear accumulation of ␤-catenin, which assembles with LEF1/TCF transcription factors and cofactors to activate Wnt target genes. Recently, the nuclear ␤-catenin complex has been shown to contain BCL9, which interacts with ␤-catenin and recruits Pygopus as a transcriptional coactivator. However, the presumed general functions of Pygopus and BCL9, which has been proposed to act as a scaffolding protein for Pygopus, have been challenged by the rather specific and modest developmental defects of targeted inactivations of both the Pygo1 and the Pygo2 genes. Here, we analyze the function of BCL9 in transcriptional activation by ␤-catenin. We find that BCL9 acts in a cell-type-specific manner and, in part, independent of Pygopus. We show that BCL9 itself contains a transcriptional activation domain in the C terminus, which functionally synergizes in lymphoid cells with the C-terminal transactivation domain of ␤-catenin. Finally, we identify amino acids in the transactivation domain of ␤-catenin that are important for its function and association with the histone acetyltransferases CBP/p300 and TRRAP/GCN5. Thus, BCL9 may serve to modulate and diversify the transcriptional responses to Wnt signaling in a cell-type-specific manner.The canonical Wnt signaling pathway regulates multiple developmental processes, including cell proliferation and cell fate decisions (reviewed in references 14 and 17). In cells that receive a Wnt signal, the key effector of the pathway, ␤-catenin, is stabilized by the inhibition of a cytosolic destruction complex, consisting of the adenomatous polyposis coli (APC) protein, axin, casein kinase I, and GSK3␤ (reviewed in reference 33). Stabilized ␤-catenin accumulates in the cytoplasm and nucleus, where it associates with members of the LEF1/ TCF family of transcription factors (reviewed in reference 63). LEF1/TCF transcription factors have no activation potential by themselves, but in association with ␤-catenin, they activate promoters containing multimerized LEF1/TCF-binding sites and natural promoters that respond to Wnt signals (6,12,22,40,44,59,61). Target gene activation depends on promoter architecture, cell type context, and the presence of specific LEF1/TCF family members. siamois and cdx1 are well-characterized Wnt target genes that are differentially activated by various LEF1/TCF proteins (8,23,28,38). Diversification of the transcriptional response by LEF1/TCF proteins was found to involve a promoter-specific activation domain in the extended carboxy (C) termini, termed the E tails, of TCF1 and TCF4 proteins (3, 21, 23).␤-Catenin is a multidomain protein consisting of 12 armadillo repeats (arm) that mediate the alternative associations with the amino (N) termini of LEF1/TCF proteins, with components of the cytosolic APC/axin destruction complex and with the membrane-bound adhesion molecule E cadherin (reviewed in reference 51). In addition, ␤-catenin contains an amino-terminal domain that regulates...