bims-unfpre Biomed News
on Unfolded protein response
Issue of 2020‒12‒27
five papers selected by
Susan Logue
University of Manitoba


  1. Cell Metab. 2020 Dec 09. pii: S1550-4131(20)30604-5. [Epub ahead of print]
    Tirosh A, Tuncman G, Calay ES, Rathaus M, Ron I, Tirosh A, Yalcin A, Lee YG, Livne R, Ron S, Minsky N, Arruda AP, Hotamisligil GS.
      Endoplasmic reticulum stress (ERS) has a pathophysiological role in obesity-associated insulin resistance. Yet, the coordinated tissue response to ERS remains unclear. Increased connexin 43 (Cx43)-mediated intercellular communication has been implicated in tissue-adaptive and -maladaptive response to various chronic stresses. Here, we demonstrate that in hepatocytes, ERS results in increased Cx43 expression and cell-cell coupling. Co-culture of ER-stressed "donor" cells resulted in intercellular transmission of ERS and dysfunction to ERS-naive "recipient" cells ("bystander response"), which could be prevented by genetic or pharmacologic suppression of Cx43. Hepatocytes from obese mice were able to transmit ERS to hepatocytes from lean mice, and mice lacking liver Cx43 were protected from diet-induced ERS, insulin resistance, and hepatosteatosis. Taken together, our results indicate that in obesity, the increased Cx43-mediated cell-cell coupling allows intercellular propagation of ERS. This novel maladaptive response to over-nutrition exacerbates the tissue ERS burden, promoting hepatosteatosis and impairing whole-body glucose metabolism.
    Keywords:  connexin 43; diabetes; endoplasmic reticulum stress; gap junctions; insulin resistance; intercellular communication; unfolded protein response
    DOI:  https://doi.org/10.1016/j.cmet.2020.11.009
  2. Mitochondrion. 2020 Dec 16. pii: S1567-7249(20)30226-9. [Epub ahead of print]
    Ali M, Boosi Narayana Rao K, Majumder P, Sarkar R, Mapa K.
      BACKGROUND: Biogenesis and function of mitochondria is profoundly dependent on cytosolic translation of mitochondrial pre-proteins and its subsequent translocation and folding inside the organelle. Continuous exposure of non-native precursor proteins, exposure to damaging by-products of oxidative phosphorylation, load of mis-targeted or misfolded proteins from neighbouring compartments and unremitting demand of communication between mitochondrial and nuclear genomes, continuously pose proteotoxic threats to the organelle. Our knowledge of cellular mechanisms to cope up with such impending threat of proteotoxicity to mitochondria, is currently evolving. In recent years, several unique response and survival pathways have been discovered shedding light on cellular strategies to cope with stressed and dysfunctional mitochondria. As mitochondria compulsorily communicate with nucleus, cytosol and endoplasmic reticulum (ER) for its own biogenesis and function and in turn maintain critical cellular processes for survival, any impairment in communication by stressed or dysfunctional mitochondria may end up with fatal consequences.DISCUSSION: and Implication: In this review, we have discussed about possible sources of mitochondrial proteotoxicity and the recent developments regarding cellular strategies to counter such stress to overcome dysfunctions of the organelle. Mitochondrial communication with neighbouring subcellular compartments like ER and cytosol during proteotoxic stress have been explored. In the context of mitochondrial proteotoxicity, alterations of crucial inter-organelle connections like ER-mitochondria contact sites and its implication on mitochondrial signaling activity like Ca2+ signaling have been dissected. Furthermore, an overview of pathological conditions, mainly neurodegenerative disorders that are known to be associated with mitochondrial proteotoxicity and Ca2+ dysregulation has been presented.
    Keywords:  Apoptosis; Ca(2+) signaling; Mitochondria; Mitochondria associated ER-membranes (MAMs); Proteotoxic Stress; Unfolded Protein Response (UPR)
    DOI:  https://doi.org/10.1016/j.mito.2020.12.003
  3. Free Radic Biol Med. 2020 Dec 18. pii: S0891-5849(20)31676-2. [Epub ahead of print]
    Zhu L, Zhou Q, He L, Chen L.
      Mitochondrial unfolded protein response (UPRmt) is a mitochondria stress response, which the transcriptional activation programs of mitochondrial chaperone proteins and proteases are initiated to maintain proteostasis in mitochondria. Additionally, the activation of UPRmt delays aging and extends lifespan by maintaining mitochondrial proteostasis. Growing evidences suggests that UPRmt plays an important role in diverse human diseases, especially ageing-related diseases. Therefore, this review focuses on the role of UPRmt in ageing and ageing-related neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease. The activation of UPRmt and the high expression of UPRmt components contribute to longevity extension. The activation of UPRmt may ameliorate Alzheimer's disease, Parkinson's disease and Huntington's disease. Besides, UPRmt is also involved in the occurrence and development of cancers and heart diseases. UPRmt contributes to the growth, invasive and metastasis of cancers. UPRmt has paradoxical roles in heart diseases. UPRmt not only protects against heart damage, but may sometimes aggravates the development of heart diseases. Considering the pleiotropic actions of UPRmt system, targeting UPRmt pathway may be a potent therapeutic avenue for neurodegenerative diseases, cancers and heart diseases.
    Keywords:  UPR(mt); ageing; cancers; diseases; heart; neurodegenerative
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2020.12.013
  4. J Cell Physiol. 2020 Dec 21.
    Sheng Y, Yang G, Markovich Z, Han SM, Xiao R.
      Proteotoxic stress is a common challenge for all organisms. Among various mechanisms involved in defending such stress, the evolutionarily conserved unfolded protein responses (UPRs) play a key role across species. Interestingly, UPRs can occur in different subcellular compartments including the endoplasmic reticulum (UPRER ), mitochondria (UPRMITO ), and cytoplasm (UPRCYTO ) through distinct mechanisms. While previous studies have shown that the UPRs are intuitively linked to organismal aging, a systematic assay on the temporal regulation of different type of UPRs during aging is still lacking. Here, using Caenorhabditis elegans (C. elegans) as the model system, we found that the endogenous UPRs (UPRER , UPRMITO , and UPRCYTO ) elevate with age, but their inducibility exhibits an age-dependent decline. Moreover, we revealed that the temporal requirements to induce different types of UPRs are distinct. Namely, while the UPRMITO can only be induced during the larval stage, the UPRER can be induced until early adulthood and the inducibility of UPRCYTO is well maintained until mid-late stage of life. Furthermore, we showed that different tissues may exhibit distinct temporal profiles of UPR inducibility during aging. Collectively, our findings demonstrate that UPRs of different subcellular compartments may have distinct temporal mechanisms during aging.
    Keywords:  aging; cytosolic UPR; endoplasmic reticulum UPR; mitochondrial UPR; stress; temporal
    DOI:  https://doi.org/10.1002/jcp.30215
  5. Cancers (Basel). 2020 Dec 17. pii: E3802. [Epub ahead of print]12(12):
    Augustin RC, Delgoffe GM, Najjar YG.
      Immunotherapy (IMT) is now a core component of cancer treatment, however, many patients do not respond to these novel therapies. Investigating the resistance mechanisms behind this differential response is now a critical area of research. Immune-based therapies, particularly immune checkpoint inhibitors (ICI), rely on a robust infiltration of T-cells into the tumor microenvironment (TME) for an effective response. While early efforts relied on quantifying tumor infiltrating lymphocytes (TIL) in the TME, characterizing the functional quality and degree of TIL exhaustion correlates more strongly with ICI response. Even with sufficient TME infiltration, immune cells face a harsh metabolic environment that can significantly impair effector function. These tumor-mediated metabolic perturbations include hypoxia, oxidative stress, and metabolites of cellular energetics. Primarily through HIF-1-dependent processes, hypoxia invokes an immunosuppressive phenotype via altered molecular markers, immune cell trafficking, and angiogenesis. Additionally, oxidative stress can promote lipid peroxidation, ER stress, and Treg dysfunction, all associated with immune dysregulation. Finally, the metabolic byproducts of lipids, amino acids, glucose, and cellular energetics are associated with immunosuppression and ICI resistance. This review will explore these biochemical pathways linked to immune cell dysfunction in the TME and highlight potential adjunctive therapies to be used alongside current IMT.
    Keywords:  cellular energetics; immunometabolism; immunotherapy
    DOI:  https://doi.org/10.3390/cancers12123802