bims-unfpre Biomed News
on Unfolded protein response
Issue of 2022–03–13
six papers selected by
Susan Logue, University of Manitoba
  1. iRhom pseudoproteases regulate ER stress-induced cell death through IP3 receptors and BCL-2.
  2. On the origin of metastases: Induction of pro-metastatic states after impending cell death via ER stress, reprogramming, and a cytokine storm.
  3. Regulation of protein secretion through chemical regulation of endoplasmic reticulum retention signal cleavage.
  4. Targeting autophagy, oxidative stress, and ER stress for neurodegenerative diseases treatment.
  5. Spliced or Unspliced, That Is the Question: The Biological Roles of XBP1 Isoforms in Pathophysiology.
  6. Destabilization of β Cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes.
  1. Nat Commun. 2022 Mar 10. 13(1): 1257
    iRhom pseudoproteases regulate ER stress-induced cell death through IP3 receptors and BCL-2.
    Iqbal Dulloo, Peace Atakpa-Adaji, Yi-Chun Yeh, Clémence Levet, Sonia Muliyil, Fangfang Lu, Colin W Taylor, Matthew Freeman.
      The folding capacity of membrane and secretory proteins in the endoplasmic reticulum (ER) can be challenged by physiological and pathological perturbations, causing ER stress. If unresolved, this leads to cell death. We report a role for iRhom pseudoproteases in controlling apoptosis due to persistent ER stress. Loss of iRhoms causes cells to be resistant to ER stress-induced apoptosis. iRhom1 and iRhom2 interact with IP3 receptors, critical mediators of intracellular Ca2+ signalling, and regulate ER stress-induced transport of Ca2+ into mitochondria, a primary trigger of mitochondrial membrane depolarisation and cell death. iRhoms also bind to the anti-apoptotic regulator BCL-2, attenuating the inhibitory interaction between BCL-2 and IP3 receptors, which promotes ER Ca2+ release. The discovery of the participation of iRhoms in the control of ER stress-induced cell death further extends their potential pathological significance to include diseases dependent on protein misfolding and aggregation.
    DOI:  https://doi.org/10.1038/s41467-022-28930-4
  2. Cell Rep. 2022 Mar 08. pii: S2211-1247(22)00223-6. [Epub ahead of print]38(10): 110490
    On the origin of metastases: Induction of pro-metastatic states after impending cell death via ER stress, reprogramming, and a cytokine storm.
    Arwen Conod, Marianna Silvano, Ariel Ruiz I Altaba.
      How metastatic cells arise is unclear. Here, we search for the induction of recently characterized pro-metastatic states as a surrogate for the origin of metastasis. Since cell-death-inducing therapies can paradoxically promote metastasis, we ask if such treatments induce pro-metastatic states in human colon cancer cells. We find that post-near-death cells acquire pro-metastatic states (PAMEs) and form distant metastases in vivo. These PAME ("let's go" in Greek) cells exhibit a multifactorial cytokine storm as well as signs of enhanced endoplasmic reticulum (ER) stress and nuclear reprogramming, requiring CXCL8, INSL4, IL32, PERK-CHOP, and NANOG. PAMEs induce neighboring tumor cells to become PAME-induced migratory cells (PIMs): highly migratory cells that re-enact the storm and enhance PAME migration. Metastases are thus proposed to originate from the induction of pro-metastatic states through intrinsic and extrinsic cues in a pro-metastatic tumoral ecosystem, driven by an impending cell-death experience involving ER stress modulation, metastatic reprogramming, and paracrine recruitment via a cytokine storm.
    Keywords:  ER stress; PAME; apoptosis; colon cancer; cytokine storm; metastasis; metastasis-initiating cells; metastatic reprogramming; primary heterogeneity; regulated cell death
    DOI:  https://doi.org/10.1016/j.celrep.2022.110490
  3. Nat Commun. 2022 Mar 14. 13(1): 1323
    Regulation of protein secretion through chemical regulation of endoplasmic reticulum retention signal cleavage.
    Arne Praznik, Tina Fink, Nik Franko, Jan Lonzarić, Mojca Benčina, Nina Jerala, Tjaša Plaper, Samo Roškar, Roman Jerala.
      Secreted proteins, such as hormones or cytokines, are key mediators in multicellular organisms. Response of protein secretion based on transcriptional control is rather slow, as it requires transcription, translation and transport from the endoplasmic reticulum (ER) to the plasma membrane via the conventional protein secretion (CPS) pathway. An alternative regulation to provide faster response would be valuable. Here we present two genetically encoded orthogonal regulatory secretion systems, which rely on the retention of pre-synthesized proteins on the ER membrane (membER, released by a cytosolic protease) or inside the ER lumen (lumER, released by an ER-luminal protease), respectively, and their release by the chemical signal-regulated proteolytic removal of an ER-retention signal, without triggering ER stress due to protein aggregates. Design of orthogonal chemically-regulated split proteases enables the combination of signals into logic functions. Its application was demonstrated on a chemically regulated therapeutic protein secretion and regulated membrane translocation of a chimeric antigen receptor (CAR) targeting cancer antigen. Regulation of the ER escape represents a platform for the design of fast-responsive and tightly-controlled modular and scalable protein secretion system for mammalian cells.
    DOI:  https://doi.org/10.1038/s41467-022-28971-9
  4. J Control Release. 2022 Mar 03. pii: S0168-3659(22)00111-0. [Epub ahead of print]
    Targeting autophagy, oxidative stress, and ER stress for neurodegenerative diseases treatment.
    Yasaman Esmaeili, Zahra Yarjanli, Fatemeh Pakniya, Elham Bidram, Marek J Los, Mehdi Eshraghi, Daniel J Klionsky, Saeid Ghavami, Ali Zarrabi.
      Protein homeostasis is a vital process for cell function and, therefore, disruption of the molecular mechanisms involved in this process, such as autophagy, may contribute to neurodegenerative diseases (NDs). Apart from autophagy disruption, excess oxidative stress and endoplasmic reticulum (ER) stress are additional main molecular mechanisms underlying neurodegeneration, leading to protein aggregation, and mitochondrial dysfunction. Notably, these primary molecular processes are interconnected pathways which have synergistic effects on each other. Therefore, we propose that targeting of the crosstalk between autophagy, oxidative stress and ER stress simultaneously may play a critical role in healing NDs. NeuroNanoTechnology, as a revolutionized approach, in combination with an in-silico strategy, holds great promise for developing de-novo structures for targeting and modulating neuro-molecular pathways. Accordingly, this review outlines the contributions of autophagy, oxidative stress, and ER stress in neurodegenerative conditions along with a particular focus on the crosstalk among these pathways. Furthermore, we provide a comprehensive discussion on the potential of nanomaterials to target this crosstalk and suggest this potential as a promising opportunity in neuroprotection.
    Keywords:  Autophagy; Endoplasmic reticulum stress; Nanotechnology; Neurodegeneration; Oxidative stress
    DOI:  https://doi.org/10.1016/j.jconrel.2022.03.001
  5. Int J Mol Sci. 2022 Mar 02. pii: 2746. [Epub ahead of print]23(5):
    Spliced or Unspliced, That Is the Question: The Biological Roles of XBP1 Isoforms in Pathophysiology.
    Xinxin Luo, Leader Alfason, Mankun Wei, Shourong Wu, Vivi Kasim.
      X-box binding protein 1 (XBP1) is a member of the CREB/ATF basic region leucine zipper family transcribed as the unspliced isoform (XBP1-u), which, upon exposure to endoplasmic reticulum stress, is spliced into its spliced isoform (XBP1-s). XBP1-s interacts with the cAMP response element of major histocompatibility complex class II gene and plays critical role in unfolded protein response (UPR) by regulating the transcriptional activity of genes involved in UPR. XBP1-s is also involved in other physiological pathways, including lipid metabolism, insulin metabolism, and differentiation of immune cells. Its aberrant expression is closely related to inflammation, neurodegenerative disease, viral infection, and is crucial for promoting tumor progression and drug resistance. Meanwhile, recent studies reported that the function of XBP1-u has been underestimated, as it is not merely a precursor of XBP1-s. Instead, XBP-1u is a critical factor involved in various biological pathways including autophagy and tumorigenesis through post-translational regulation. Herein, we summarize recent research on the biological functions of both XBP1-u and XBP1-s, as well as their relation to diseases.
    Keywords:  physiological and pathological pathways; post-translational modification; spliced XBP1 (XBP1-s); transcriptional activator; unspliced XBP1 (XBP1-u)
    DOI:  https://doi.org/10.3390/ijms23052746
  6. Proc Natl Acad Sci U S A. 2022 03 15. 119(11): e2113074119
    Destabilization of β Cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes.
    Xiaofeng Zheng, Qing Wei Calvin Ho, Minni Chua, Olga Stelmashenko, Xin Yi Yeo, Sneha Muralidharan, Federico Torta, Elaine Guo Yan Chew, Michelle Mulan Lian, Jia Nee Foo, Sangyong Jung, Sunny Hei Wong, Nguan Soon Tan, Nanwei Tong, Guy A Rutter, Markus R Wenk, David L Silver, Per-Olof Berggren, Yusuf Ali.
      SignificanceWith obesity on the rise, there is a growing appreciation for intracellular lipid droplet (LD) regulation. Here, we show how saturated fatty acids (SFAs) reduce fat storage-inducing transmembrane protein 2 (FIT2)-facilitated, pancreatic β cell LD biogenesis, which in turn induces β cell dysfunction and death, leading to diabetes. This mechanism involves direct acylation of FIT2 cysteine residues, which then marks the FIT2 protein for endoplasmic reticulum (ER)-associated degradation. Loss of β cell FIT2 and LDs reduces insulin secretion, increases intracellular ceramides, stimulates ER stress, and exacerbates diet-induced diabetes in mice. While palmitate and stearate degrade FIT2, unsaturated fatty acids such as palmitoleate and oleate do not, results of which extend to nutrition and diabetes.
    Keywords:  ER stress; FIT2; diet-induced diabetes; lipid droplets; pancreatic β cells
    DOI:  https://doi.org/10.1073/pnas.2113074119
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