bims-ershed 2023-02-26 papers

Issue of 2023‒02‒26
five papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

Arch Biochem Biophys. 2023 Feb 22. pii: S0003-9861(23)00051-6. [Epub ahead of print] 109552

XBP1s acts as a transcription factor of IRE1α and promotes proliferation of colon cancer cells.

Shuting Liu, Qiang Gao, Yuyao Li, Jie Lun, Mengchao Yu, Hongwei Zhang, Jing Fang.

Upon ER stress, IRE1α is activated to splice XBP1 mRNA to generate XBP1s, a transcription factor that induces the expression of genes to cope with the stress. Expression of IRE1α is elevated in cancers and the IRE1α-XBP1s axis plays an important role in proliferation of cancer cells. However, the underlying mechanism is not well known. We found that ER stressors induced the expression of IRE1α, which was inhibited by depletion of XBP1s. XBP1s bound IRE1α promoter and initiated the transcription of IRE1α. These data indicate that XBP1s acts as a transcription factor of IRE1α. Overexpression of XBP1s increased the phosphorylation of JNK, a substrate of IRE1α kinase, which was inhibited by IRE1α kinase inhibitor Kira8. Overexpression of XBP1s also activated the regulated IRE1-dependent decay of mRNAs, which was suppressed by IRE1α RNase inhibitor STF083010. Moreover, we found that expression of XBP1s promoted proliferation of colon cancer cells, which was abrogated by Kira8 and STF083010. The results suggest that XBP1s functions to induce IRE1α expression and promote cancer cell proliferation. Our findings reveal a previously unknown mechanism of IRE1α expression by XBP1s and highlight the role of this regulation in proliferation of colon cancer cells, suggesting that IRE1α-targeting is a potential therapeutic strategy for colon cancer.

Keywords: Cell proliferation; Colon cancer; ER stress; IRE1α; XBP1s

DOI: https://doi.org/10.1016/j.abb.2023.109552

J Biol Chem. 2023 Feb 15. pii: S0021-9258(23)00163-1. [Epub ahead of print] 103031

ER stress induces upregulation of transcription factor Tbx20 and downstream Bmp2 signaling to promote cardiomyocyte survival.

Shreya Das, Arunima Mondal, Chandrani Dey, Santanu Chakraborty, Rudranil Bhowmik, Sanmoy Karmakar, Arunima Sengupta.

In the mammalian heart, fetal cardiomyocytes proliferates prior to birth; however, they exit the cell cycle shortly after birth. Recent studies show adult cardiomyocytes re-enters the cell cycle post-injury to promote cardiac regeneration. The endoplasmic reticulum (ER) orchestrates the production and assembly of different types of proteins, and a disruption in this machinery leads to the generation of ER stress which activates the unfolded protein response (UPR). There is a very fine balance between ER stress-mediated protective and pro-apoptotic responses. For example, T-box transcription factor 20 (Tbx20), a member of the Tbx1 subfamily of T-box genes, promotes embryonic and adult cardiomyocyte proliferation post-injury to restore cardiac homeostasis. However, the function and regulatory interactions of Tbx20 in ER stress-induced cardiomyopathy have not yet been reported . We show here that ER stress upregulates Tbx20, which further activates downstream Bmp2/pSmad1/5/8 signaling to induce cardiomyocyte proliferation and limit apoptosis. However, augmenting ER stress reverses this protective response. We also show that increased expression of tbx20 during ER stress is mediated by the Atf6 arm of the UPR. Cardiomyocyte-specific loss of Tbx20 results in decreased cardiomyocyte proliferation and increased apoptosis. Administration of recombinant Bmp2 protein during ER stress upregulates Tbx20 leading to augmented proliferation, indicating a feed-forward loop mechanism. In in vivo ER stress, as well as in diabetic cardiomyopathy, we found the activity of Tbx20 is increased with concomitant increased cardiomyocyte proliferation and decreased apoptosis. These data support a critical role of Tbx20/Bmp2 signaling in promoting cardiomyocyte survival during ER stress-induced cardiomyopathies.

Keywords: ER stress; Tbx20; apoptosis; cardiomyopathy; proliferation

DOI: https://doi.org/10.1016/j.jbc.2023.103031

Cell Death Differ. 2023 Feb 22.

The p53 endoplasmic reticulum stress-response pathway evolved in humans but not in mice via PERK-regulated p53 mRNA structures.

Leila Fusée, Norman Salomao, Anand Ponnuswamy, Lixiao Wang, Ignacio López, Sa Chen, Xiaolian Gu, Stavros Polyzoidis, Sivakumar Vadivel Gnanasundram, Robin Fahraeus.

Cellular stress conditions activate p53-dependent pathways to counteract the inflicted damage. To achieve the required functional diversity, p53 is subjected to numerous post-translational modifications and the expression of isoforms. Little is yet known how p53 has evolved to respond to different stress pathways. The p53 isoform p53/47 (p47 or ΔNp53) is linked to aging and neural degeneration and is expressed in human cells via an alternative cap-independent translation initiation from the 2nd in-frame AUG at codon 40 (+118) during endoplasmic reticulum (ER) stress. Despite an AUG codon in the same location, the mouse p53 mRNA does not express the corresponding isoform in either human or mouse-derived cells. High-throughput in-cell RNA structure probing shows that p47 expression is attributed to PERK kinase-dependent structural alterations in the human p53 mRNA, independently of eIF2α. These structural changes do not take place in murine p53 mRNA. Surprisingly, PERK response elements required for the p47 expression are located downstream of the 2nd AUG. The data show that the human p53 mRNA has evolved to respond to PERK-mediated regulation of mRNA structures in order to control p47 expression. The findings highlight how p53 mRNA co-evolved with the function of the encoded protein to specify p53-activities under different cellular conditions.

DOI: https://doi.org/10.1038/s41418-023-01127-y

Front Cell Dev Biol. 2023 ;11 1023327

Obesity impacts placental function through activation of p-IRE1a-XBP1s signaling.

Wei-Bin Shen, Bingbing Wang, Ruofan Yao, Katherine R Goetzinger, Sheng Wu, Haijun Gao, Peixin Yang.

Maternal obesity is associated with a variety of obstetrical outcomes including stillbirth, preeclampsia, and gestational diabetes, and increases the risk of fetuses for congenital heart defects. Obesity during pregnancy represents a major contribution to metabolic dysregulation, which not only plays a key role in the pathogenesis of adverse outcome but also can potently induce endoplasmic reticulum (ER) stress. However, the mechanism associating such an obesogenic metabolic environment and adverse pregnancy outcomes has remained poorly understood. In this study, we aimed to determine whether the ER stress pathways (also named unfolded protein response (UPR)) were activated in the placenta by obesity. We collected placenta from the obese pregnancy (n = 12) and non-obese pregnancy (n = 12) following delivery by Caesarean-section at term. The specimens were assessed with immunocytochemistry staining and RT-QPCR. Our results revealed that in the obese placenta, p-IRE1α and XBP1s were significantly increased, CHOP and nine UPR chaperone genes were upregulated, including GRP95, PDIA6, Calnexin, p58IPK, SIL-1, EDEM, Herp, GRP58 and Calreticulin. However, Perk and BiP are not activated in the obese placenta. Our data suggest that upregulated p-IRE1α and XBP1s signaling, and UPR chaperone genes may play an important role in maternal obesity-induced placental pathology. In conclusion, this is the first report on ER stress and UPR activation in the placenta of maternal obesity. Our findings represent the first step in the understanding of one of the key ER signaling pathways, also referred to IRE1α-XBP1, in placental pathophysiology affected by obesity, which may be an important mechanism accounting for the observed higher maternal and perinatal risks.

Keywords: IRE1α; XBP1S; chaperones; endoplasmic reticulum stress; maternal obese; placenta

DOI: https://doi.org/10.3389/fcell.2023.1023327

J Cell Biol. 2023 Mar 06. pii: e202206008. [Epub ahead of print]222(3):

PERK recruits E-Syt1 at ER-mitochondria contacts for mitochondrial lipid transport and respiration.

Maria Livia Sassano, Alexander R van Vliet, Ellen Vervoort, Sofie Van Eygen, Chris Van den Haute, Benjamin Pavie, Joris Roels, Johannes V Swinnen, Marco Spinazzi, Leen Moens, Kristina Casteels, Isabelle Meyts, Paolo Pinton, Saverio Marchi, Leila Rochin, Francesca Giordano, Blanca Felipe-Abrio, Patrizia Agostinis.

The integrity of ER-mitochondria appositions ensures transfer of ions and phospholipids (PLs) between these organelles and exerts crucial effects on mitochondrial bioenergetics. Malfunctions within the ER-mitochondria contacts altering lipid trafficking homeostasis manifest in diverse pathologies, but the molecular effectors governing this process remain ill-defined. Here, we report that PERK promotes lipid trafficking at the ER-mitochondria contact sites (EMCS) through a non-conventional, unfolded protein response-independent, mechanism. PERK operates as an adaptor for the recruitment of the ER-plasma membrane tether and lipid transfer protein (LTP) Extended-Synaptotagmin 1 (E-Syt1), within the EMCS. In resting cells, the heterotypic E-Syt1-PERK interaction endorses transfer of PLs between the ER and mitochondria. Weakening the E-Syt1-PERK interaction or removing the lipid transfer SMP-domain of E-Syt1, compromises mitochondrial respiration. Our findings unravel E-Syt1 as a PERK interacting LTP and molecular component of the lipid trafficking machinery of the EMCS, which critically maintains mitochondrial homeostasis and fitness.

DOI: https://doi.org/10.1083/jcb.202206008