In mammals, the prototypical endoplasmic reticulum (ER) stress sensor inositol-requiring enzyme 1 (IRE1) has diverged into two paralogs. IRE1α is broadly expressed and mediates the unconventional splicing of X-box binding protein 1 (XBP1) mRNA during ER stress. By contrast, IRE1β is expressed selectively in the digestive tract, and its function remains unclear. Here, we report that IRE1β plays a distinctive role in mucin-secreting goblet cells. In IRE1β −/− mice, aberrant mucin 2 (MUC2) accumulated in the ER of goblet cells, accompanied by ER distension and elevated ER stress signaling such as increased XBP1 mRNA splicing. In contrast, conditional IRE1α −/− mice showed no such ER distension but a marked decrease in spliced XBP1 mRNA. mRNA stability assay revealed that MUC2 mRNA was greatly stabilized in IRE1β −/− mice. These findings suggest that in goblet cells, IRE1β, but not IRE1α, promotes efficient protein folding and secretion in the ER by optimizing the level of mRNA encoding their major secretory product, MUC2.inflammatory bowel disease | unfolded protein response

Edited by Robert Barouki Keywords:Endoplasmic reticulum stress Unfolded protein response IRE1b Secretory proteins a b s t r a c t Accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes ER stress. The ER stress sensor inositol requiring enzyme-1beta (IRE1b), which is specifically expressed in intestinal epithelial cells, is thought to be involved in translational repression. However, its mechanism of action is not fully understood. Using a reporter that can evaluate and distinguish between translation efficiency in the cytosol and on the ER membrane, we show here that IRE1b represses translation on the ER membrane but not in the cytosol, and that this selective repression depends on the RNase activity of IRE1b.

[Structure: see text] A novel alicyclic chiral C2-symmetric piperazine, (S,S)-7, is designed and synthesized from L-proline. Benzoylation of a series of cyclic and acyclic meso-1,2-diols with a catalytic amount of (S,S)-7 and CuCl2 provided optically active monobenzoates with high enantioselectivity.

Polypodanes constitute a new class of bicyclic triterpenoids and their occurrence in nature is important for the mechanistic study of the biosynthesis of polycyclic triterpenoids. (ϩ)-a-Polypodatetraene (1) and (ϩ)-g-polypodatetraene (2) are the first compound of this class and were isolated from the fresh leaves of Polypodium fauriei and Lemmaphyllum microphyllum for (1), and Polystichum ovatopaleaceum and P. polyblephalum for (2), respectively. 1)Their planar structures were established to be polypoda-8(26),13,17,21-tetraene (1) and polypoda-7,13,17,21-tetraene (2) by a careful analysis of 1 H-, 13 C-NMR, IR, and massspectral data.1) The absolute structure of the natural (ϩ)-apolypodatetraene (ϩ)-1 is determined as depicted in 1 because the optical rotation shows opposite signs, [a] D ϩ27.4°f or the natural (ϩ)-1 and [a] D Ϫ18.9°for the synthetic ent-1 derived from copalic acid (3).2) On the other hand, the absolute structure of the natural (ϩ)-g-polypodatetraene (2) was assumed by comparison of optical rotation between 1, 21) Total synthesis of (Ϯ)-1 was reported based on mercury(II)trifluoromethanesulphonate-amine complex-induced olefin cyclization, 3) while total synthesis of (ϩ)-1 and (ϩ)-2 was not reported so far. We previously reported that enantioselective acetylation of (Ϯ)-albicanol (6) in the presence of isopropenyl acetate using lipase PL-266 from Alcaligenes sp. gave (ϩ)-albicanyl acetate (7) (Ͼ99% ee) and (Ϫ)-albicanol (6) (Ͼ99% ee). Reductive deprotection of acetyl group in (ϩ)-7 afforded the natural (ϩ)-albicanol (6), which was treated with BF 3 · Et 2 O to provide the natural (Ϫ)-drimenol (8).4) In this paper, we describe the first synthesis of the natural (ϩ)-a-polypodatetraene (1) from (ϩ)-6 and (ϩ)-g-polypodatetraene (2) from (Ϫ)-8, and the determination of the absolute structure of (ϩ)-2. Results and DiscussionSynthesis of (؉)-a a-Polypodatetraene (1) from (؉)-Albicanol (6) The method of elongation of the carbon chain from the primary alcohol group of (ϩ)-6 was developed stepwise by the following synthetic sequence. Mesylation of (ϩ)-6 in pyridine gave the mesylate 9 (99%), which was treated with NaCN in dimethyl sulfoxide (DMSO) to afford the nitrile compound 10 (49%) along with diexo-olefin 11 (31%). Reduction of 10 with diisobutylaluminum hydride (DIBAL) in toluene furnished the aldehyde 12 in 89% yield, which was reduced with NaBH 4 to provide the alcohol 13 in quantitative yield. Bromination of 13 using carbon tetrabromide (CBr 4 ) and triphenylphosphine (Ph 3 P) under neutral conditions gave the corresponding bromide 14, which was treated with NaCN in DMSO to provide the nitrile 15 in 71% overall yield. Dibal-H reduction of 15 yielded an aldehyde 16 (82%), which was reacted with (carbethoxyethylidene)triphenylphosphorane to give selectively (E)-17 in quantitative yield. Dibal-H reduction of (E)-17 gave an allyl alcohol 18 in quantitative yield, which was treated with tosyl chloride to afford the allyl chloride 19 in 43% yield. The prepared 19 was immediately treated with sodium benzen...