bims-unfpre 2024-04-21 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2024–04–21
eight papers selected by
Susan Logue, University of Manitoba

ER stress signaling at the interphase between MASH and hepatocellular carcinoma.
IRE1 signaling increases PERK expression during chronic ER stress.
HLA-B*57:01-dependent intracellular stress in keratinocytes triggers dermal hypersensitivity reactions to abacavir.
Endoplasmic reticulum stress: bridging inflammation and obesity-associated adipose tissue.
Endothelial Mitochondria-Associated Membranes (MAMs) Isolation by Percoll Step Gradients.
Identification of a novel RNA transcript TISPL upregulated by stressors that stimulate ATF4.
The Multifaceted Role of Intracellular Glycosylation in Cytoprotection and Heart Disease.
Caspase-mediated processing of TRBP regulates apoptosis during viral infection.

Hepatology. 2024 Apr 16.

ER stress signaling at the interphase between MASH and hepatocellular carcinoma.

Younis Hazari, Eric Chevet, Béatrice Bailly-Maitre, Claudio Hetz.

Hepato-cellular carcinoma (HCC) is the most frequent primary liver cancer with an extremely poor prognosis and often develops on preset of chronic liver diseases. Major risk factors for HCC include metabolic dysfunction-associated steatohepatitis (MASH), a complex multifactorial condition associated with abnormal endoplasmic reticulum (ER) proteostasis. To cope with ER stress, the unfolded protein response (UPR) engages adaptive reactions to restore the secretory capacity of the cell. Recent advances revealed that ER stress signaling plays a critical role in HCC progression. Here we propose that chronic ER stress is a common transversal factor contributing to the transition from liver disease (risk factor) to HCC. Interventional strategies to target the UPR in HCC as cancer therapy are also discussed.

DOI: https://doi.org/10.1097/HEP.0000000000000893
Cell Death Dis. 2024 Apr 18. 15(4): 276

IRE1 signaling increases PERK expression during chronic ER stress.

Gideon Ong, Rosemund Ragetli, Katarzyna Mnich, Bradley W Doble, Wafa Kammouni, Susan E Logue.

The Unfolded Protein Response (UPR) is an essential cellular process activated by the accumulation of unfolded proteins within the Endoplasmic Reticulum (ER), a condition referred to as ER stress. Three ER anchored receptors, IRE1, PERK and ATF6 act as ER stress sensors monitoring the health of the ER. Upon detection of ER stress, IRE1, PERK and ATF6 initiate downstream signaling pathways collectively referred to as the UPR. The overarching aim of the UPR is to restore ER homeostasis by reducing ER stress, however if that is not possible, the UPR transitions from a pro-survival to a pro-death response. While our understanding of the key signaling pathways central to the UPR is well defined, the same is not true of the subtle signaling events that help fine tune the UPR, supporting its ability to adapt to varying amplitudes or durations of ER stress. In this study, we demonstrate cross talk between the IRE1 and PERK branches of the UPR, wherein IRE1 via XBP1s signaling helps to sustain PERK expression during prolonged ER stress. Our findings suggest cross talk between UPR branches aids adaptiveness thereby helping to support the plasticity of UPR signaling responses.

DOI: https://doi.org/10.1038/s41419-024-06663-0
PNAS Nexus. 2024 Apr;3(4): pgae140

HLA-B*57:01-dependent intracellular stress in keratinocytes triggers dermal hypersensitivity reactions to abacavir.

Akira Kazaoka, Sota Fujimori, Yushiro Yamada, Tomohiro Shirayanagi, Yuying Gao, Saki Kuwahara, Naoki Sakamoto, Takeshi Susukida, Shigeki Aoki, Kousei Ito.

  Specific human leukocyte antigen (HLA) polymorphisms combined with certain drug administration strongly correlate with skin eruption. Abacavir hypersensitivity (AHS), which is strongly associated with HLA-B*57:01, is one of the most representative examples. Conventionally, HLA transmits immunological signals via interactions with T cell receptors on the cell surface. This study focused on HLA-mediated intracellular reactions in keratinocytes that might determine the onset of skin immunotoxicity by drug treatments. Abacavir exposure resulted in keratinocytes expressing HLA-B*57:01 exhibiting endoplasmic reticulum (ER) stress responses, such as immediate calcium release into the cytosol and enhanced HSP70 expression. In contrast, keratinocytes expressing HLA-B*57:03 (closely related to HLA-B*57:01) did not show these changes. This indicated that HLA-B*57:01 has a specific intracellular response to abacavir in keratinocytes in the absence of lymphocytes. Furthermore, abacavir exposure in HLA-B*57:01-expressing keratinocytes elevated the expression of cytokines/chemokines such as interferon-γ, interleukin-1β, and CCL27, and induced T lymphoblast migration. These effects were suppressed by ER stress relief using 4-phenylbutyrate (4-PB). HLA-B*57:01-transgenic mice also exhibited ER stress in epidermal areas following abacavir administration, and abacavir-induced skin toxicity was attenuated by the administration of 4-PB. Moreover, abacavir bound to HLA-B*57:01 within cells and its exposure led to HLA-B*57:01 protein aggregation and interaction with molecular chaperones in the ER of keratinocytes. Our results underscore the importance of HLA-mediated intracellular stress responses in understanding the onset of HLA-B*57:01-mediated AHS. We provide the possibility that the intracellular behavior of HLA is crucial for determining the onset of drug eruptions.

Keywords:  HLA; abacavir; drug eruption; endoplasmic reticulum stress; keratinocytes

DOI:  https://doi.org/10.1093/pnasnexus/pgae140
Front Immunol. 2024 ;15 1381227

Endoplasmic reticulum stress: bridging inflammation and obesity-associated adipose tissue.

Kaile Ma, Yanjiao Zhang, Jingyi Zhao, Lijuan Zhou, Min Li.

  Obesity presents a significant global health challenge, increasing the susceptibility to chronic conditions such as diabetes, cardiovascular disease, and hypertension. Within the context of obesity, lipid metabolism, adipose tissue formation, and inflammation are intricately linked to endoplasmic reticulum stress (ERS). ERS modulates metabolism, insulin signaling, inflammation, as well as cell proliferation and death through the unfolded protein response (UPR) pathway. Serving as a crucial nexus, ERS bridges the functionality of adipose tissue and the inflammatory response. In this review, we comprehensively elucidate the mechanisms by which ERS impacts adipose tissue function and inflammation in obesity, aiming to offer insights into targeting ERS for ameliorating metabolic dysregulation in obesity-associated chronic diseases such as hyperlipidemia, hypertension, fatty liver, and type 2 diabetes.

Keywords:  adipose tissue; endoplasmic reticulum stress; inflammation; metabolic disorder; obesity

DOI:  https://doi.org/10.3389/fimmu.2024.1381227
Methods Mol Biol. 2024 ;2782 113-122

Endothelial Mitochondria-Associated Membranes (MAMs) Isolation by Percoll Step Gradients.

Margaret Baldini, Cheng Zhang, Jun Yu.

  Mitochondria-associated membranes (MAMs) are regions where the endoplasmic reticulum (ER) interacts with mitochondria and regulate lipid trafficking, calcium signaling, ER stress, and inflammation activation. Isolation of MAMs from endothelial cells is vital for studying insight into the immune regulation of many inflammatory diseases. Endothelial cells (ECs) are critical innate immune cells due to their paracrine function of secreting interleukins, chemokines, cytokines, and growth factors, as well as expressing levels of pattern recognition receptors including toll-like receptors (TLRs). Furthermore, ECs regulate and recruit monocytes by expressing adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), P-selectin, and E-selectin, to facilitate monocyte diapedesis in areas of damage and inflammation. This protocol consists of step-by-step instructions on isolating pure MAMs and other subcellular fractions from endothelial cells, which is critical to understanding ER and mitochondria crosstalks in endothelial functions in health and disease.

Keywords:  Endoplasmic reticulum; Endothelial cells; Immunity; Inflammation; Mitochondria; Mitochondria-associated membranes; Subcellular fractions

DOI:  https://doi.org/10.1007/978-1-0716-3754-8_8
Gene. 2024 Apr 12. pii: S0378-1119(24)00345-7. [Epub ahead of print]917 148464

Identification of a novel RNA transcript TISPL upregulated by stressors that stimulate ATF4.

Yutaro Wakabayashi, Aika Shimono, Yuki Terauchi, Chao Zeng, Michiaki Hamada, Kentaro Semba, Shinya Watanabe, Kosuke Ishikawa.

  Cells sense, respond, and adapt to environmental conditions that cause stress. In a previous study using HeLa cells, we isolated reporter cells responding to the endoplasmic reticulum (ER) stress inducers, thapsigargin and tunicamycin, using a highly sensitive promoter trap vector system. Splinkerette PCR and 5' rapid amplification of cDNA ends (5' RACE) identified a novel transcript that is upregulated by ER stress. Its endogenous expression increased approximately 10-fold in response to thapsigargin and tunicamycin within 1 h, but was down-regulated after 4 h. Because the transcript starts from an intron of a long noncoding RNA known as LINC-PINT, we designated the newly identified transcript TISPL (transcript induced by stressors from LINC-PINTlocus). TISPL was also expressed under several other stress conditions. It was particularly increased > 10-fold upon glucose starvation and 7-fold by arsenite exposure. Furthermore, in silico analyses, including a ChIP-atlas search, revealed that there is an ATF4-binding region with a c/ebp-Atf response element (CARE) downstream of the transcription start site of TISPL. Based on these results, we hypothesized that TISPL may be induced by the phospho-eIF2α and ATF4- axis of the integrated stress response pathway, which is known to be activated by the stress conditions listed above. As expected, knockout of ATF4 abolished the stress-induced upregulation of TISPL. Our results indicate that TISPL may be a useful biomarker for detecting stress conditions that activate ATF4. Our highly sensitive trap vector system proved beneficial in discovering new biomarkers.

Keywords:  ATF4; Biomarker; Endoplasmic reticulum stress; Integrated stress response; long noncoding RNA

DOI:  https://doi.org/10.1016/j.gene.2024.148464
J Biol Chem. 2024 Apr 17. pii: S0021-9258(24)01797-6. [Epub ahead of print] 107296

The Multifaceted Role of Intracellular Glycosylation in Cytoprotection and Heart Disease.

Priya Umapathi, Akanksha Aggarwal, Fiddia Zahra, Bhargavi Narayanan, Natasha E Zachara.

  The modification of nuclear, cytoplasmic, and mitochondrial proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) is an essential post-translational modification common in metazoans. O-GlcNAc is cycled on and off proteins in response to environmental and physiological stimuli impacting protein function, which, in turn, tunes pathways that include transcription, translation, proteostasis, signal transduction, and metabolism. One class of stimulus that induces rapid and dynamic changes to O-GlcNAc is cellular injury, resulting from environmental stress (for instance, heat shock), hypoxia/reoxygenation injury, ischemia reperfusion injury (heart attack, stroke, trauma hemorrhage), and sepsis. Acute elevation of O-GlcNAc before or after injury reduces apoptosis and necrosis, suggesting that injury-induced changes in O-GlcNAcylation regulate cell fate decisions. However, prolonged elevation or reduction in O-GlcNAc leads to a maladaptive response and is associated with pathologies such as hypertrophy and heart failure. In this review, we discuss the impact of O-GlcNAc in both acute and prolonged models of injury with a focus on the heart and biological mechanisms that underpin cell survival.

Keywords:  Autophagy; Cardioprotection; Cellular Stress Response; Chaperone; ER Stress; Glycoprotein; Heart Failure; Hypertrophy; Integrated Stress Response

DOI:  https://doi.org/10.1016/j.jbc.2024.107296
Nucleic Acids Res. 2024 Apr 19. pii: gkae246. [Epub ahead of print]

Caspase-mediated processing of TRBP regulates apoptosis during viral infection.

Keiko Shibata, Harune Moriizumi, Koji Onomoto, Yuka Kaneko, Takuya Miyakawa, Shuhei Zenno, Masaru Tanokura, Mitsutoshi Yoneyama, Tomoko Takahashi, Kumiko Ui-Tei.

RNA silencing is a post-transcriptional gene-silencing mechanism mediated by microRNAs (miRNAs). However, the regulatory mechanism of RNA silencing during viral infection is unclear. TAR RNA-binding protein (TRBP) is an enhancer of RNA silencing that induces miRNA maturation by interacting with the ribonuclease Dicer. TRBP interacts with a virus sensor protein, laboratory of genetics and physiology 2 (LGP2), in the early stage of viral infection of human cells. Next, it induces apoptosis by inhibiting the maturation of miRNAs, thereby upregulating the expression of apoptosis regulatory genes. In this study, we show that TRBP undergoes a functional conversion in the late stage of viral infection. Viral infection resulted in the activation of caspases that proteolytically processed TRBP into two fragments. The N-terminal fragment did not interact with Dicer but interacted with type I interferon (IFN) signaling modulators, such as protein kinase R (PKR) and LGP2, and induced ER stress. The end results were irreversible apoptosis and suppression of IFN signaling. Our results demonstrate that the processing of TRBP enhances apoptosis, reducing IFN signaling during viral infection.

DOI: https://doi.org/10.1093/nar/gkae246