bims-ershed Biomed News
on ER Stress in Health and Diseases
Issue of 2022–02–06
nine papers selected by
Matías Eduardo González Quiroz, Worker’s Hospital
  1. Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity.
  2. The cap-proximal RNA secondary structure inhibits pre-initiation complex formation on HAC1 mRNA.
  3. HBXIP is a novel regulator of the unfolded protein response that sustains tamoxifen resistance in ER+ breast cancer.
  4. The unfolded protein response and the biology of uveal melanoma.
  5. Architecture of the endoplasmic reticulum plays a role in proteostasis.
  6. The protein-folding problem: Not yet solved.
  7. Cohesin in DNA damage response and double-strand break repair.
  8. Crosstalk between different DNA repair pathways for DNA double strand break repairs.
  9. Insights into protein-DNA interactions from hydrogen bond energy-based comparative protein-ligand analyses.
  1. Nat Commun. 2022 Feb 01. 13(1): 608
    Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity.
    Aparajita Madhavan, Bernard P Kok, Bibiana Rius, Julia M D Grandjean, Adekunle Alabi, Verena Albert, Ara Sukiasyan, Evan T Powers, Andrea Galmozzi, Enrique Saez, R Luke Wiseman.
      In obesity, signaling through the IRE1 arm of the unfolded protein response exerts both protective and harmful effects. Overexpression of the IRE1-regulated transcription factor XBP1s in liver or fat protects against obesity-linked metabolic deterioration. However, hyperactivation of IRE1 engages regulated IRE1-dependent decay (RIDD) and TRAF2/JNK pro-inflammatory signaling, which accelerate metabolic dysfunction. These pathologic IRE1-regulated processes have hindered efforts to pharmacologically harness the protective benefits of IRE1/XBP1s signaling in obesity-linked conditions. Here, we report the effects of a XBP1s-selective pharmacological IRE1 activator, IXA4, in diet-induced obese (DIO) mice. IXA4 transiently activates protective IRE1/XBP1s signaling in liver without inducing RIDD or TRAF2/JNK signaling. IXA4 treatment improves systemic glucose metabolism and liver insulin action through IRE1-dependent remodeling of the hepatic transcriptome that reduces glucose production and steatosis. IXA4-stimulated IRE1 activation also enhances pancreatic function. Our findings indicate that systemic, transient activation of IRE1/XBP1s signaling engenders multi-tissue benefits that integrate to mitigate obesity-driven metabolic dysfunction.
    DOI:  https://doi.org/10.1038/s41467-022-28271-2
  2. J Biol Chem. 2022 Jan 28. pii: S0021-9258(22)00088-6. [Epub ahead of print] 101648
    The cap-proximal RNA secondary structure inhibits pre-initiation complex formation on HAC1 mRNA.
    Jagadeesh Kumar Uppala, Leena Sathe, Abhijit Chakraborty, Sankhajit Bhattacharjee, Anthony Thomas Pulvino, Madhusudan Dey.
      Translation of HAC1 mRNA in the budding yeast Saccharomyces cerevisiae is de-repressed when RNase Ire1 removes its intron via non-conventional cytosolic splicing in response to accumulation of unfolded proteins inside the endoplasmic reticulum. The spliced HAC1 mRNA is translated into a transcription factor that changes the cellular gene expression patterns to increase the protein folding capacity of cells. Previously, we showed that a segment of the intronic sequence interacts with the 5'-untranslated region (5'-UTR) of the un-spliced mRNA, resulting in repression of HAC1 translation at the initiation stage. However, the exact mechanism of translational de-repression is not clear. Here, we show that at least 11-base-pairing interactions between the 5'-UTR and intron are sufficient to repress HAC1 translation. We also show that over-expression of the helicase eIF4A de-repressed translation of an un-spliced HAC1 mRNA containing only 11-base-pair interactions between the 5'-UTR and intronic sequences. Additionally, our genetic screen identifies that single mutations in the 5'-UTR•intron interaction site could de-repress translation of the un-spliced HAC1 mRNA. Furthermore, we show that the addition of 24 RNA bases between the mRNA 5'-cap and the 5'-UTR•intron interaction site de-repressed translation of the un-spliced HAC1 mRNA. Together, our data provide a mechanistic explanation for why the cap-proximal 5'-UTR•intron RNA duplex inhibits the recruitment of translating ribosomes to HAC1 mRNA, thus keeping mRNA translationally repressed.
    Keywords:  ER; Eukaryotic translation initiation; Hac1; Ire1; UPR
    DOI:  https://doi.org/10.1016/j.jbc.2022.101648
  3. J Biol Chem. 2022 Jan 27. pii: S0021-9258(22)00084-9. [Epub ahead of print] 101644
    HBXIP is a novel regulator of the unfolded protein response that sustains tamoxifen resistance in ER+ breast cancer.
    Shenghong Zhang, Ranran Wang, Xinyue Wang, Xueling Guo, Yanyan Du, Xin Guo, Xinlan Zong, Changhui Zhu, Xiaolei Zhou.
      Endocrine therapy-resistant estrogen receptor-positive (ER+) breast cancer cells often exhibit an augmented capacity to maintain endoplasmic reticulum (EnR) homeostasis under adverse conditions. Oncoprotein hepatitis B X-interacting protein (HBXIP) is a known transcriptional coactivator that promotes cancer development. However, it is unclear whether HBXIP participates in maintaining EnR homeostasis and promoting drug-resistance in ER+ breast cancer. Here, we report that tamoxifen-resistant (TmaR) breast cancer cells exhibit increased expression of HBXIP, which acts as an inactivator of the unfolded protein response (UPR) to diminish tamoxifen (TAM)-induced EnR stress. We show that HBXIP deficiency promotes EnR-associated degradation (ERAD), enhances UPR-element (UPRE) reporter activity and cellular oxidative stress, and ultimately attenuates the growth of TmaR cells in vitro and in vivo. Mechanistically, we demonstrate that HBXIP acts as a chaperone of UPR transducer inositol-requiring enzyme 1a (IRE1α) and diminishes production of reactive oxygen species (ROS) in TamR breast cancer cells. Upon loss of HBXIP expression, TAM treatment hyperactivates IRE1α and its downstream proapoptotic pathways and simultaneously induces accumulation of intracellular ROS. This elevated ROS programmatically activates the other two branches of the UPR, mediated by PKR-like ER kinase (PERK) and activating transcription factor 6α (ATF6α). Clinical investigations and Kaplan-Meier plotter analysis revealed that HBXIP is highly expressed in TamR breast cancer tissues. Furthermore, reinforced HBXIP expression associated with a high recurrence and poor relapse-free survival rates in tamoxifen monotherapy ER+ breast cancer patients. These findings indicate that HBXIP is a novel regulator of EnR homeostasis and a potential target for TamR breast cancer therapy.
    Keywords:  Breast cancer; Endoplasmic reticulum stress; HBXIP; Tamoxifen resistance; Unfolded protein response
    DOI:  https://doi.org/10.1016/j.jbc.2022.101644
  4. Biochimie. 2022 Jan 27. pii: S0300-9084(22)00027-X. [Epub ahead of print]
    The unfolded protein response and the biology of uveal melanoma.
    Stanley Zhang, Ke Wang, Xue Zhu, Svetlana Cherepanoff, R Max Conway, Michele C Madigan, Ling Zhu, Michael Murray, Fanfan Zhou.
      Uveal melanoma (UM) is a highly metastatic ocular cancer that arises from the melanocytes of the uveal tract (the choroid, ciliary body and iris). Despite a growing understanding of UM biology, effective systemic treatments are currently lacking and the cancer has an extremely poor prognosis. Therefore, identifying novel agents that act by new tumorigenic mechanisms in UM is essential to address this unmet clinical need. Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the organelle, and the unfolded protein response (UPR) is the cellular mechanism that is activated so that cells may adapt to the situation. Dysregulated UPR signaling has been detected in UM tumors and has been associated with an increase in immune evasion and metastatic activity. A number of established and novel oncology drugs act in part by modulating ER stress and the UPR. The induction of protein-folding stress and the UPR could be a novel approach for the development of new therapeutics in UM. Further studies are now warranted to understand the mechanisms and consequences of UPR signaling in UM.
    Keywords:  Cancer; Endoplasmic reticulum stress; Metastasis; Tumor microenvironment; Unfolded protein response; Uveal melanoma
    DOI:  https://doi.org/10.1016/j.biochi.2022.01.017
  5. Autophagy. 2022 Jan 31. 1-2
    Architecture of the endoplasmic reticulum plays a role in proteostasis.
    Smriti Parashar, Susan Ferro-Novick.
      The endoplasmic reticulum (ER) forms a contiguous network of tubules and sheets. When errors in protein folding occur, misfolded proteins accumulate in the ER. Proteostasis can be restored by ER quality control pathways. Reticulophagy is an ER quality control pathway that uses resident autophagy receptors to link an ER domain to the autophagy machinery. We recently showed that the reticulophagy receptor RTN3L recruits the COPII cargo adaptor SEC24C to target disease-causing mutant proinsulin INS2Akita puncta to the lysosome for degradation. When reticulophagy is disrupted and delivery to the lysosome is blocked, large INS2Akita puncta accumulate in the ER. Photobleach analysis revealed that these puncta behave like liquid condensates and not aggregates, as previously suggested. Other reticulophagy substrates that are segregated into tubules behave like INS2Akita, whereas a substrate of the ER sheets receptor, RETREG1/FAM134B, appears to be less fluid. Large INS2Akita puncta also accumulate when ER sheets are proliferated by the loss of LNPK, or by overproduction of the sheets-producing protein, CKAP4/CLIMP63. Restoring the tubular network by overexpressing reticulons reverses this phenotype. Our findings revealed that fluid-like deleterious cargoes are segregated into tubules to prevent them from expanding and affecting cell health while they are waiting to undergo reticulophagy.
    Keywords:  ER structure; Lunapark; SEC24C; misfolded prohormones and neuropeptides; protein quality control; reticulophagy
    DOI:  https://doi.org/10.1080/15548627.2022.2030175
  6. Science. 2022 Feb 04. 375(6580): 507
    The protein-folding problem: Not yet solved.
    Peter B Moore, Wayne A Hendrickson, Richard Henderson, Axel T Brunger.
      
    DOI:  https://doi.org/10.1126/science.abn9422
  7. Crit Rev Biochem Mol Biol. 2022 Feb 03. 1-18
    Cohesin in DNA damage response and double-strand break repair.
    Wenya Hou, Yan Li, Jiaxin Zhang, Yisui Xia, Xueting Wang, Hongxiang Chen, Huiqiang Lou.
      Cohesin, a four-subunit ring comprising SMC1, SMC3, RAD21 and SA1/2, tethers sister chromatids by DNA replication-coupled cohesion (RC-cohesion) to guarantee correct chromosome segregation during cell proliferation. Postreplicative cohesion, also called damage-induced cohesion (DI-cohesion), is an emerging critical player in DNA damage response (DDR). In this review, we sum up recent progress on how cohesin regulates the DNA damage checkpoint activation and repair pathway choice, emphasizing postreplicative cohesin loading and DI-cohesion establishment in yeasts and mammals. DI-cohesion and RC-cohesion show distinct features in many aspects. DI-cohesion near or far from the break sites might undergo different regulations and execute different tasks in DDR and DSB repair. Furthermore, some open questions in this field and the significance of this new scenario to our understanding of genome stability maintenance and cohesinopathies are discussed.
    Keywords:  Chromatin; DNA damage response (DDR); DNA damage-induced cohesion; double-strand break (DSB); sister chromatid cohesion
    DOI:  https://doi.org/10.1080/10409238.2022.2027336
  8. Mutat Res Genet Toxicol Environ Mutagen. 2022 Jan;pii: S1383-5718(21)00129-7. [Epub ahead of print]873 503438
    Crosstalk between different DNA repair pathways for DNA double strand break repairs.
    Jung-Min Oh, Kyungjae Myung.
      DNA double strand breaks (DSBs) are the most threatening type of DNA lesions and must be repaired properly in order to inhibit severe diseases and cell death. There are four major repair pathways for DSBs: non-homologous end joining (NHEJ), homologous recombination (HR), single strand annealing (SSA) and alternative end joining (alt-EJ). Cells choose repair pathway depending on the cell cycle phase and the length of 3' end of the DNA when DSBs are generated. Blunt and short regions of the 5' or 3' overhang DNA are repaired by NHEJ, which uses direct ligation or limited resection processing of the broken DNA end. In contrast, HR, SSA and alt-EJ use the resected DNA generated by the MRN (MRE11-RAD50-NBS1) complex and C-terminal binding protein interacting protein (CtIP) activated during the S and G2 phases. Here, we review recent findings on each repair pathway and the choice of repair mechanism and highlight the role of mismatch repair (MMR) protein in HR.
    Keywords:  DNA double strand break repair; DNA end resection; HR; MMEJ; NHEJ
    DOI:  https://doi.org/10.1016/j.mrgentox.2021.503438
  9. Proteins. 2022 Feb 04.
    Insights into protein-DNA interactions from hydrogen bond energy-based comparative protein-ligand analyses.
    Fareeha K Malik, Jun-Tao Guo.
      Hydrogen bonds play important roles in protein folding and protein-ligand interactions, particularly in specific protein-DNA recognition. However, the distributions of hydrogen bonds, especially hydrogen bond energy in different types of protein-ligand complexes, is unknown. Here we performed a comparative analysis of hydrogen bonds among three non-redundant datasets of protein-protein, protein-peptide and protein-DNA complexes. Besides comparing the number of hydrogen bonds in terms of types and locations, we investigated the distributions of hydrogen bond energy. Our results indicate that while there is no significant difference of hydrogen bonds within protein chains among the three types of complexes, interfacial hydrogen bonds are significantly more prevalent in protein-DNA complexes. More importantly, the interfacial hydrogen bonds in protein-DNA complexes displayed a unique energy distribution of strong and weak hydrogen bonds whereas majority of the interfacial hydrogen bonds in protein-protein and protein-peptide complexes are of predominantly high strength with low energy. Moreover, there is a significant difference in the energy distributions of minor groove hydrogen bonds between protein-DNA complexes with different binding specificity. Highly specific protein-DNA complexes contain more strong hydrogen bonds in the minor groove than multi-specific complexes, suggesting important role of minor groove in specific protein-DNA recognition. These results can help better understand protein-DNA interactions and have important implications in improving quality assessments of protein-DNA complex models.
    Keywords:  binding specificity; hydrogen bond energy; minor groove; protein-DNA; protein-ligand
    DOI:  https://doi.org/10.1002/prot.26313
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