BBF2H7, a Novel Transmembrane bZIP Transcription Factor, Is a New Type of Endoplasmic Reticulum Stress Transducer

Abstract

Endoplasmic reticulum (ER) stress transducers IRE1 (inositol requiring 1), PERK (PKR-like endoplasmic reticulum kinase), and ATF6 (activating transcription factor 6) are well known to transduce signals from the ER to the cytoplasm and nucleus when unfolded proteins accumulate in the ER. Recently, we identified OASIS (old astrocyte specifically induced substance) as a novel ER stress transducer expressed in astrocytes. We report here that BBF2H7 (BBF2 human homolog on chromosome 7), an ER-resident transmembrane protein with the bZIP domain in the cytoplasmic portion and structurally homologous to OASIS, is cleaved at the membrane in response to ER stress. The cleaved fragments of BBF2H7 translocate into the nucleus and can bind directly to cyclic AMP-responsive element sites to activate transcription of target genes. Interestingly, although BBF2H7 protein is not expressed under normal conditions, it is markedly induced at the translational level during ER stress, suggesting that BBF2H7 might contribute to only the late phase of unfolded protein response signaling. In a mouse model of focal brain ischemia, BBF2H7 protein is prominently induced in neurons in the peri-infarction region. Furthermore, in a neuroblastoma cell line, BBF2H7 overexpression suppresses ER stress-induced cell death, while small interfering RNA knockdown of BBF2H7 promotes ER stress-induced cell death. Taken together, our results suggest that BBF2H7 is a novel ER stress transducer and could play important roles in preventing accumulation of unfolded proteins in damaged neurons.

FUS-CREB3L2/L1–Positive Sarcomas Show a Specific Gene Expression Profile with Upregulation of CD24 and FOXL1

“…Gene expression array (cases [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], IHC analyses (cases 1, 2, 10, 11, and 20-24), ICC (cases 5 and 6), and/or SNP array (cases 1-9) were carried out on 24 LGFMS cases listed in Table 1. The clinical, cytogenetic, and fusion transcript data on 20 of the cases have been published before (5)(6)(7)(8).…”

“…However, the knowledge about the target genes of wt CREB3L2/L1, and the transcriptional networks or cellular pathways involved, is very limited. Nevertheless, as CREB3L2 and CREB3L2DTM, which lacks the transmembrane and luminal domains and corresponds to the cleaved fragment, seem to preferentially bind CRE sites (11), it is reasonable to hypothesize that CREB3L2 and FUS-CREB3L2 regulate genes that contain active CRE sites in their promoters.…”

“…9). On ER stress, the cleaved fragment which contains the bZIP domain is translocated to the nucleus where it may activate transcription more potently than the full-length protein through binding box-B sequences, ER stress-responsive elements, or cyclic AMP responsive elements (CRE) in the enhancers or promoters of target genes (10)(11)(12)(13). Previous data suggest that the FUS-CREB3L2 chimera is localized to the ER, cleaved by intramembrane proteolysis, and capable of activating transcription through box-B and CRE sequences and that it is a stronger transcriptional activator than wild-type (wt) CREB3L2 (13).…”

Physiological unfolded protein response regulated by OASIS family members, transmembrane bZIP transcription factors

“…On examining the tissue localization of BBF2H7, it is most strongly expressed is in the proliferating zone of the cartilage in developing long bones (20). Bbf2h7 is also expressed in the lungs, spleen, gonad and nervous system (12) although not expressed at all in osseous tissues (20).…”

“…BBF2H7 is a transmembrane transcription factor that is closely similar in structure to OASIS (Fig. 1), and is also cleaved at the membrane region by RIP in response to ER stress (12). Where it differs from OASIS is in its expression patterns.…”