bims-unfpre Biomed News
on Unfolded protein response
Issue of 2023–07–30
six papers selected by
Susan Logue, University of Manitoba



  1. Proc Natl Acad Sci U S A. 2023 08;120(31): e2303448120
      Cancer cells are commonly subjected to endoplasmic reticulum (ER) stress. To gain survival advantage, cancer cells exploit the adaptive aspects of the unfolded protein response such as upregulation of the ER luminal chaperone GRP78. The finding that when overexpressed, GRP78 can escape to other cellular compartments to gain new functions regulating homeostasis and tumorigenesis represents a paradigm shift. Here, toward deciphering the mechanisms whereby GRP78 knockdown suppresses EGFR transcription, we find that nuclear GRP78 is prominent in cancer and stressed cells and uncover a nuclear localization signal critical for its translocation and nuclear activity. Furthermore, nuclear GRP78 can regulate expression of genes and pathways, notably those important for cell migration and invasion, by interacting with and inhibiting the activity of the transcriptional repressor ID2. Our study reveals a mechanism for cancer cells to respond to ER stress via transcriptional regulation mediated by nuclear GRP78 to adopt an invasive phenotype.
    Keywords:  ER stress; GRP78; lung cancer; nuclear translocation; transcriptional regulation
    DOI:  https://doi.org/10.1073/pnas.2303448120
  2. Nat Aging. 2023 Jul 27.
      Animals rely on chemosensory cues to survive in pathogen-rich environments. In Caenorhabditis elegans, pathogenic bacteria trigger aversive behaviors through neuronal perception and activate molecular defenses throughout the animal. This suggests that neurons can coordinate the activation of organism-wide defensive responses upon pathogen perception. In this study, we found that exposure to volatile pathogen-associated compounds induces activation of the endoplasmic reticulum unfolded protein response (UPRER) in peripheral tissues after xbp-1 splicing in neurons. This odorant-induced UPRER activation is dependent upon DAF-7/transforming growth factor beta (TGF-β) signaling and leads to extended lifespan and enhanced clearance of toxic proteins. Notably, rescue of the DAF-1 TGF-β receptor in RIM/RIC interneurons is sufficient to significantly recover UPRER activation upon 1-undecene exposure. Our data suggest that the cell non-autonomous UPRER rewires organismal proteostasis in response to pathogen detection, pre-empting proteotoxic stress. Thus, chemosensation of particular odors may be a route to manipulation of stress responses and longevity.
    DOI:  https://doi.org/10.1038/s43587-023-00467-1
  3. Elife. 2023 Jul 25. pii: e83884. [Epub ahead of print]12
      Changes in lipid metabolism are associated with aging and age-related diseases, including proteopathies. The endoplasmic reticulum (ER) is uniquely a major hub for protein and lipid synthesis, making its function essential for both protein and lipid homeostasis. However, it is less clear how lipid metabolism and protein quality may impact each other. Here, we identified let-767, a putative hydroxysteroid dehydrogenase in Caenorhabditis elegans, as an essential gene for both lipid and ER protein homeostasis. Knockdown of let-767 reduces lipid stores, alters ER morphology in a lipid-dependent manner, and blocks induction of the Unfolded Protein Response of the ER (UPRER). Interestingly, a global reduction in lipogenic pathways restores UPRER induction in animals with reduced let-767. Specifically, we find that supplementation of 3-oxoacyl, the predicted metabolite directly upstream of let-767, is sufficient to block induction of the UPRER. This study highlights a novel interaction through which changes in lipid metabolism can alter a cell's response to protein-induced stress.
    Keywords:  C. elegans; ER UPR; cell biology; genetics; genomics; lipid homeostasis; proteostasis; stress response
    DOI:  https://doi.org/10.7554/eLife.83884
  4. Haematologica. 2023 Jul 27.
      Leukemia stem cells (LSCs) requires frequent adaptation to maintenance self-renewal ability despite they are longer exposure to cell-intrinsic and cell-extrinsic stresses. However, the mechanism by which LSCs maintain their leukemogenic activities and how individual LSCs respond to stress remain poorly understood. Herein, we found that DNAJC10, a member of HSP40 family, was frequently upregulated in various types of acute myeloid leukemia (AML) and in LSC-enriched cells. Deficiency of DNAJC10 leads to a dramatic increase in the apoptosis of both human leukemia cell lines and LSCs enriched populations. Although DNAJC10 is not required for normal hematopoiesis, deficiency of Dnajc10 significantly abrogated AML development and suppressed self-renewal of LSCs in the MLL-AF9-induced murine leukemia model. Mechanistically, inhibition of DNAJC10 specifically induces endoplasmic reticulum (ER) stress and promotes activating of PERK-EIF2α-ATF4 branch of unfolded protein response (UPR). Blocking PERK by GSK2606414 (PERKi) or shRNA rescued the loss of function of DNAJC10 both in vitro and in vivo. Importantly, deficiency of DNAJC10 increased sensitivity of AML cells to daunorubicin (DNR) and cytarabine (Ara-C). These data revealed that DNAJC10 functions as an oncogene in MLL-AF9-induced AML via regulating PERK branch of the UPR. DNAJC10 may be an ideal therapeutic target for eliminating LSCs and improving the effectiveness of DNR and Ara-C.
    DOI:  https://doi.org/10.3324/haematol.2023.282691
  5. Proc Natl Acad Sci U S A. 2023 Aug;120(31): e2218865120
      Extreme environmental conditions eventually limit plant growth [J. R. Dinneny, Annu. Rev. Cell Dev. Biol. 35, 1-19 (2019), N. Gigli-Bisceglia, C. Testerink, Curr. Opin. Plant Biol. 64, 102120 (2021)]. Here, we reveal a mechanism that enables multiple external cues to get integrated into auxin-dependent growth programs in Arabidopsis thaliana. Our forward genetics approach on dark-grown hypocotyls uncovered that an imbalance in membrane lipids enhances the protein abundance of PIN-LIKES (PILS) [E. Barbez et al., Nature 485, 119 (2012)] auxin transport facilitators at the endoplasmic reticulum (ER), which thereby limits nuclear auxin signaling and growth rates. We show that this subcellular response relates to ER stress signaling, which directly impacts PILS protein turnover in a tissue-dependent manner. This mechanism allows PILS proteins to integrate environmental input with phytohormone auxin signaling, contributing to stress-induced growth adaptation in plants.
    Keywords:  PIN-LIKES; auxin; endoplasmic reticulum; membrane lipids; protein turnover
    DOI:  https://doi.org/10.1073/pnas.2218865120
  6. Dev Cell. 2023 Jul 24. pii: S1534-5807(23)00306-4. [Epub ahead of print]58(14): 1219-1220
      In a recent issue of Nature, González et al. and Foronda et al. examine the role of ubiquitin in autophagic capture of ER by ER-phagy. They propose that ubiquitylation of ER-phagy receptor FAM134B and ER-shaping protein ARL61PL1 promotes receptor clustering in nanodomains, which generates membrane curvature, facilitating autophagosomal capture.
    DOI:  https://doi.org/10.1016/j.devcel.2023.06.008