bims-unfpre Biomed News
on Unfolded protein response
Issue of 2024–06–16
eight papers selected by
Susan Logue, University of Manitoba
  1. The endoplasmic reticulum connects to the nucleus by constricted junctions that mature after mitosis.
  2. Endoplasmic Reticulum Stress Response Mediator IRE-1α Promotes Host Dendritic Cells in Graft-versus-Host Disease Development.
  3. Overactivation of XBP1 in plasma cells implies worse survival through innate immunity in esophageal squamous cell carcinoma.
  4. Estrogen counteracts age-related decline in beige adipogenesis through the NAMPT-regulated ER stress response.
  5. JEV infection leads to dysfunction of lysosome by downregulating the expression of LAMP1 and LAMP2.
  6. Inhibition of a cyclic nucleotide-gated channel on neuronal cilia activates unfolded protein response in intestinal cells to promote longevity.
  7. Deacetylated MDH1 and IDH1 aggravates PANoptosis in acute liver failure through endoplasmic reticulum stress signaling.
  8. ER-mitochondria association negatively affects wound healing by regulating NLRP3 activation.
  1. EMBO Rep. 2024 Jun 14.
    The endoplasmic reticulum connects to the nucleus by constricted junctions that mature after mitosis.
    Helena Bragulat-Teixidor, Keisuke Ishihara, Gréta Martina Szücs, Shotaro Otsuka.
      Junctions between the endoplasmic reticulum (ER) and the outer membrane of the nuclear envelope (NE) physically connect both organelles. These ER-NE junctions are essential for supplying the NE with lipids and proteins synthesized in the ER. However, little is known about the structure of these ER-NE junctions. Here, we systematically study the ultrastructure of ER-NE junctions in cryo-fixed mammalian cells staged in anaphase, telophase, and interphase by correlating live cell imaging with three-dimensional electron microscopy. Our results show that ER-NE junctions in interphase cells have a pronounced hourglass shape with a constricted neck of 7-20 nm width. This morphology is significantly distinct from that of junctions within the ER network, and their morphology emerges as early as telophase. The highly constricted ER-NE junctions are seen in several mammalian cell types, but not in budding yeast. We speculate that the unique and highly constricted ER-NE junctions are regulated via novel mechanisms that contribute to ER-to-NE lipid and protein traffic in higher eukaryotes.
    Keywords:  Correlative Light-electron Microscopy; Endoplasmic Reticulum; Membrane Contact Site; Nuclear Envelope; Open Mitosis
    DOI:  https://doi.org/10.1038/s44319-024-00175-w
  2. J Immunol. 2024 Jun 12. pii: ji2300616. [Epub ahead of print]
    Endoplasmic Reticulum Stress Response Mediator IRE-1α Promotes Host Dendritic Cells in Graft-versus-Host Disease Development.
    Hee-Jin Choi, Yongxia Wu, Brianyell McDaniel Mims, Allison Pugel, Chih-Hang Anthony Tang, Linlu Tian, Chih-Chi Andrew Hu, Xue-Zhong Yu.
      Allogeneic hematopoietic cell transplantation is an effective treatment for hematologic malignancies, but the complications such as graft-versus-host disease (GVHD) can limit its benefit. The conditioning regimens before transplant, including chemotherapy or irradiation, can trigger endoplasmic reticulum stress. IRE-1α is a major endoplasmic reticulum stress mediator that can further activate both spliced XBP-1 (XBP-1s) and regulated IRE-1-dependent decay (RIDD). IRE-1α-XBP-1s signaling controls dendritic cell (DC) differentiation and Ag presentation, crucial in GVHD progression. In this study, we used DC-specific XBP-1-deficient mice as donors or recipients and observed that XBP-1s was crucial for host DCs in the induction of GVHD but dispensable for the graft-versus-leukemia response. To specifically target IRE-1α in the host, we treated recipient mice with the IRE-1α inhibitor B-I09 for 3 d prior to bone marrow transplantation, which significantly suppressed GVHD development while maintaining the graft-versus-leukemia effect. XBP-1-deficient or BI09-treated recipients showed reduced DC survival after irradiation and bone marrow transplantation. Inhibition of IRE-1α also led to a reduction in DC alloreactivity, subsequently decreasing the proliferation and activation of allogeneic T cells. With further study using RIDD-deficient DCs, we observed that RIDD was also required for optimal DC activation. Taken together, XBP-1s and RIDD both promote host DC survival and alloreactivity that contribute to GVHD development.
    DOI:  https://doi.org/10.4049/jimmunol.2300616
  3. Cancer Lett. 2024 Jun 11. pii: S0304-3835(24)00439-7. [Epub ahead of print] 217045
    Overactivation of XBP1 in plasma cells implies worse survival through innate immunity in esophageal squamous cell carcinoma.
    Yin Yin, Yuhao Wang, Xiao Yu, Yang Li, Yahui Zhao, Zhihua Liu.
      To maintain protein homeostasis, X-box binding protein 1 (XBP1) undergoes splicing following the activation of the unfolded protein response (UPR) in response to endoplasmic reticulum (ER) stress. Although targeting ER stress represents a promising therapeutic strategy, a comprehensive understanding of XBP1 at the cellular level and the link between XBP1 and the innate nervous system is lacking. Here, TCGA pancancer datasets from 33 cancer types, scRNA pancancer datasets from 454 patients and bulk RNA-seq datasets from 155 paired esophageal squamous cell carcinoma (ESCC) patients were analyzed. To cope with ER stress, plasma cells tend to activate XBP1 after undergoing bacterial infection and inflammatory signaling from the innate immune system. Patients with high XBP1 expression in their plasma cells have a higher tumor grade and worse survival. However, activation of the innate immune system with increased XBP1 expression in plasma cells correlates with an increased lymphocyte ratio, indicative of a more robust immune response. Moreover, XBP1 activation appears to initiate leukocyte migration at the transcriptional level. Our study revealed that the XBP1-induced UPR could mediate the crosstalk between optimal acquired humoral immune responses and innate immunity in ESCC.
    Keywords:  ESCC; NK cells; XBP1; monocytes; plasma cells
    DOI:  https://doi.org/10.1016/j.canlet.2024.217045
  4. Nat Aging. 2024 Jun 10.
    Estrogen counteracts age-related decline in beige adipogenesis through the NAMPT-regulated ER stress response.
    Jooman Park, Ruoci Hu, Yanyu Qian, Shaolei Xiong, Asma Sana El-Sabbagh, Meram Ibrahim, Jaden Wang, Ziqiao Xu, Zhengjia Chen, Qing Song, Zhenyuan Song, Gege Yan, Abeer M Mahmoud, Yanlin He, Brian T Layden, Jiwang Chen, Sang-Ging Ong, Pingwen Xu, Yuwei Jiang.
      Thermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages that they offer are compromised with aging. Here we show that treating mice with estrogen (E2), a hormone that decreases with age, can counteract the age-related decline in beige adipogenesis when exposed to cold temperature while concurrently enhancing energy expenditure and improving glucose tolerance in mice. Mechanistically, we found that nicotinamide phosphoribosyl transferase (NAMPT) plays a pivotal role in facilitating the formation of E2-induced beige adipocytes, which subsequently suppresses the onset of age-related endoplasmic reticulum (ER) stress. Furthermore, we found that targeting NAMPT signaling, either genetically or pharmacologically, can restore the formation of beige adipocytes by increasing the number of perivascular adipocyte progenitor cells. Conversely, the absence of NAMPT signaling prevents this process. Together, our findings shed light on the mechanisms regulating the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT-controlled ER stress pathway as a key regulator of this process.
    DOI:  https://doi.org/10.1038/s43587-024-00633-z
  5. Vet Microbiol. 2024 Jun 06. pii: S0378-1135(24)00172-X. [Epub ahead of print]295 110150
    JEV infection leads to dysfunction of lysosome by downregulating the expression of LAMP1 and LAMP2.
    Xingmiao Yang, Zheng Wang, Shengda Xie, Zhenjie Liang, Ning Wei, Junhui Pan, Yundi Zhao, Ruibing Cao.
      Japanese Encephalitis Virus (JEV), the predominant cause of viral encephalitis in many Asian countries, affects approximately 68,000 people annually. Lysosomes are dynamic structures that regulate cellular metabolism by mediating lysosomal biogenesis and autophagy. Here, we showed that lysosome-associated membrane protein 1 (LAMP1) and LAMP2 were downregulated in cells after JEV infection, resulting in a decrease in the quantity of acidified lysosomes and impaired lysosomal catabolism. What's more, JEV nonstructural protein 4B plays key roles in the reduction of LAMP1/2 via the autophagy-lysosome pathway. JEV NS4B also promoted abnormal aggregation of SLA-DR, an important component of the swine MHC-II molecule family involved in antigen presentation and CD4+ cell activation initiation. Mechanistically, NS4B localized to the ER during JEV infection and interacted with GRP78, leading to the activation of ER stress-mediated autophagy. The 131-204 amino acid (aa) region of NS4B is essential for autophagy induction and LAMP1/2 reduction. In summary, our findings reveal a novel pathway by which JEV induces autophagy and disrupts lysosomal function.
    Keywords:  Autophagy; JEV; LAMP1; LAMP2; Lysosome; NS4B; SLA-DR
    DOI:  https://doi.org/10.1016/j.vetmic.2024.110150
  6. Proc Natl Acad Sci U S A. 2024 Jun 18. 121(25): e2321228121
    Inhibition of a cyclic nucleotide-gated channel on neuronal cilia activates unfolded protein response in intestinal cells to promote longevity.
    Dongdong Li, Di Chen, Wei Li, Guangshuo Ou.
      Ciliary defects are linked to ciliopathies, but impairments in the sensory cilia of Caenorhabditis elegans neurons extend lifespan, a phenomenon with previously unclear mechanisms. Our study reveals that neuronal cilia defects trigger the unfolded protein response of the endoplasmic reticulum (UPRER) within intestinal cells, a process dependent on the insulin/insulin-like growth factor 1 (IGF-1) signaling transcription factor and the release of neuronal signaling molecules. While inhibiting UPRER doesn't alter the lifespan of wild-type worms, it normalizes the extended lifespan of ciliary mutants. Notably, deactivating the cyclic nucleotide-gated (CNG) channel TAX-4 on the ciliary membrane promotes lifespan extension through a UPRER-dependent mechanism. Conversely, constitutive activation of TAX-4 attenuates intestinal UPRER in ciliary mutants. Administering a CNG channel blocker to worm larvae activates intestinal UPRER and increases adult longevity. These findings suggest that ciliary dysfunction in sensory neurons triggers intestinal UPRER, contributing to lifespan extension and implying that transiently inhibiting ciliary channel activity may effectively prolong lifespan.
    Keywords:  CNG channel; UPRER; lifespan; neuronal cilia
    DOI:  https://doi.org/10.1073/pnas.2321228121
  7. Cell Death Discov. 2024 Jun 08. 10(1): 275
    Deacetylated MDH1 and IDH1 aggravates PANoptosis in acute liver failure through endoplasmic reticulum stress signaling.
    Chunxia Shi, Yukun Wang, Jin Guo, Danmei Zhang, Yanqiong Zhang, Zuojiong Gong.
      Acute liver failure (ALF) is a disease with a high mortality rate and poor prognosis, whose pathogenesis is not fully understood. PANoptosis is a recently proposed mode of cell death characterized by pyroptosis, apoptosis, and necroptosis, but it cannot be explained by any of them alone. This study aims to explore the role of PANoptosis in ALF and the impact and mechanism of deacetylated malate dehydrogenase 1 (MDH1) and isocitrate dehydrogenase 1 (IDH1) on PANoptosis. Our results found that, compared with the control group, the cell viability in the lipopolysaccharide (LPS)/D-galactosamine (D-Gal) group decreased, lactate dehydrogenase (LDH) release increased, cell death increased, and the levels of PANoptosis-related molecules RIPK1, GSDMD, caspase-3, MLKL, IL-18, IL-1β increased, indicating that PANoptosis increased during ALF. Deacetylated MDH1 at K118 and IDH1 at K93 increased the expression of PANoptosis-related molecules RIPK1, GSDMD, caspase-3, MLKL, IL-18, and IL-1β in vivo and in vitro. The deacetylation weakened the inhibitory effect of histone deacetylase (HDAC) inhibitor ACY1215 on PANoptosis-related molecules, suggesting that deacetylated MDH1 at K118 and IDH1 at K93 aggravated PANoptosis during ALF. Deacetylated MDH1 at K118 and IDH1 at K93 also promoted the expression of endoplasmic reticulum stress-related molecules BIP, ATF6, XBP1, and CHOP in vivo and in vitro. The use of endoplasmic reticulum stress inhibitor 4-PBA weakened the promotion effect of deacetylated MDH1 K118 and IDH1 K93 on PANoptosis. The results suggested that deacetylated MDH1 at K118 and IDH1 at K93 may aggravate PANoptosis in ALF through endoplasmic reticulum stress signaling. In conclusion, deacetylated MDH1 and IDH1 may aggravate PANoptosis in ALF, and the mechanism may act through endoplasmic reticulum stress signaling.
    DOI:  https://doi.org/10.1038/s41420-024-02054-8
  8. Cell Death Dis. 2024 Jun 11. 15(6): 407
    ER-mitochondria association negatively affects wound healing by regulating NLRP3 activation.
    Caterina Licini, Gianluca Morroni, Guendalina Lucarini, Veronica Angela Maria Vitto, Fiorenza Orlando, Sonia Missiroli, Gloria D'Achille, Mariasole Perrone, Tatiana Spadoni, Laura Graciotti, Giorgia Bigossi, Mauro Provinciali, Annamaria Offidani, Monica Mattioli-Belmonte, Oscar Cirioni, Paolo Pinton, Oriana Simonetti, Saverio Marchi.
      Methicillin-resistant Staphylococcus aureus (MRSA) is the most common causative agent of acute bacterial skin and skin-structure infections (ABSSSI), one of the major challenges to the health system worldwide. Although the use of antibiotics as the first line of intervention for MRSA-infected wounds is recommended, important side effects could occur, including cytotoxicity or immune dysregulation, thus affecting the repair process. Here, we show that the oxazolidinone antibiotic linezolid (LZD) impairs wound healing by aberrantly increasing interleukin 1 β (IL-1β) production in keratinocytes. Mechanistically, LZD triggers a reactive oxygen species (ROS)-independent mitochondrial damage that culminates in increased tethering between the endoplasmic reticulum (ER) and mitochondria, which in turn activates the NLR family pyrin domain-containing 3 (NLRP3) inflammasome complex by promoting its assembly to the mitochondrial surface. Downregulation of ER-mitochondria contact formation is sufficient to inhibit the LZD-driven NLRP3 inflammasome activation and IL-1β production, restoring wound closure. These results identify the ER-mitochondria association as a key factor for NLRP3 activation and reveal a new mechanism in the regulation of the wound healing process that might be clinically relevant.
    DOI:  https://doi.org/10.1038/s41419-024-06765-9
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