bims-ershed 2022-12-11 papers

Issue of 2022‒12‒11
five papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

mBio. 2022 Dec 08. e0306822

The IRE1α-XBP1 Signaling Axis Promotes Glycolytic Reprogramming in Response to Inflammatory Stimuli.

Bevin C English, Hannah P Savage, Scott P Mahan, Vladimir E Diaz-Ochoa, Briana M Young, Basel H Abuaita, Gautam Sule, Jason S Knight, Mary X O'Riordan, Andreas J Bäumler, Renée M Tsolis.

Immune cells must be able to adjust their metabolic programs to effectively carry out their effector functions. Here, we show that the endoplasmic reticulum (ER) stress sensor Inositol-requiring enzyme 1 alpha (IRE1α) and its downstream transcription factor X box binding protein 1 (XBP1) enhance the upregulation of glycolysis in classically activated macrophages (CAMs). The IRE1α-XBP1 signaling axis supports this glycolytic switch in macrophages when activated by lipopolysaccharide (LPS) stimulation or infection with the intracellular bacterial pathogen Brucella abortus. Importantly, these different inflammatory stimuli have distinct mechanisms of IRE1α activation; while Toll-like receptor 4 (TLR4) supports glycolysis under both conditions, TLR4 is required for activation of IRE1α in response to LPS treatment but not B. abortus infection. Though IRE1α and XBP1 are necessary for maximal induction of glycolysis in CAMs, activation of this pathway is not sufficient to increase the glycolytic rate of macrophages, indicating that the cellular context in which this pathway is activated ultimately dictates the cell's metabolic response and that IRE1α activation may be a way to fine-tune metabolic reprogramming. IMPORTANCE The immune system must be able to tailor its response to different types of pathogens in order to eliminate them and protect the host. When confronted with bacterial pathogens, macrophages, frontline defenders in the immune system, switch to a glycolysis-driven metabolism to carry out their antibacterial functions. Here, we show that IRE1α, a sensor of ER stress, and its downstream transcription factor XBP1 support glycolysis in macrophages during infection with Brucella abortus or challenge with Salmonella LPS. Interestingly, these stimuli activate IRE1α by independent mechanisms. While the IRE1α-XBP1 signaling axis promotes the glycolytic switch, activation of this pathway is not sufficient to increase glycolysis in macrophages. This study furthers our understanding of the pathways that drive macrophage immunometabolism and highlights a new role for IRE1α and XBP1 in innate immunity.

Keywords: Brucella; endoplasmic reticulum; immunometabolism; innate immunity

DOI: https://doi.org/10.1128/mbio.03068-22

iScience. 2022 Dec 22. 25(12): 105626

BRCA1 mediates protein homeostasis through the ubiquitination of PERK and IRE1.

Robert Hromas, Gayathri Srinivasan, Ming Yang, Aruna Jaiswal, Taylor A Totterdale, Linda Phillips, Austin Kirby, Nazli Khodayari, Mark Brantley, Elizabeth A Williamson, Kimi Y Kong.

Tumors with BRCA1 mutations have poor prognoses due to genomic instability. Yet this genomic instability has risks and BRCA1-deficient (def) cancer cells must develop pathways to mitigate these risks. One such risk is the accumulation of unfolded proteins in BRCA1-def cancers from increased mutations due to their loss of genomic integrity. Little is known about how BRCA1-def cancers survive their genomic instability. Here we show that BRCA1 is an E3 ligase in the endoplasmic reticulum (ER) that targets the unfolded protein response (UPR) stress sensors, Eukaryotic Translation Initiation Factor 2-alpha Kinase 3 (PERK) and Serine/Threonine-Protein Kinase/Endoribonuclease Inositol-Requiring Enzyme 1 (IRE1) for ubiquitination and subsequent proteasome-mediated degradation. When BRCA1 is mutated or depleted, both PERK and IRE1 protein levels are increased, resulting in a constitutively activated UPR. Furthermore, the inhibition of protein folding or UPR signaling markedly decreases the overall survival of BRCA1-def cancer cells. Our findings define a mechanism used by the BRCA1-def cancer cells to survive their increased unfolded protein burden which can be used to develop new therapeutic strategies to treat these cancers.

Keywords: Cancer; Cell biology; Functional aspects of cell biology

DOI: https://doi.org/10.1016/j.isci.2022.105626

Mol Neurobiol. 2022 Dec 07.

Endoplasmic Reticulum Stress-Regulated Chaperones as a Serum Biomarker Panel for Parkinson's Disease.

Katarzyna Mnich, Shirin Moghaddam, Patrick Browne, Timothy Counihan, Stephen P Fitzgerald, Kenneth Martin, Ciaran Richardson, Afshin Samali, Adrienne M Gorman.

Examination of post-mortem brain tissues has previously revealed a strong association between Parkinson's disease (PD) pathophysiology and endoplasmic reticulum (ER) stress. Evidence in the literature regarding the circulation of ER stress-regulated factors released from neurons provides a rationale for investigating ER stress biomarkers in the blood to aid diagnosis of PD. The levels of ER stress-regulated proteins in serum collected from 29 PD patients and 24 non-PD controls were measured using enzyme-linked immunosorbent assays. A panel of four biomarkers, protein disulfide-isomerase A1, protein disulfide-isomerase A3, mesencephalic astrocyte-derived neurotrophic factor, and clusterin, together with age and gender had higher ability (area under the curve 0.64, sensitivity 66%, specificity 57%) and net benefit to discriminate PD patients from the non-PD group compared with other analyzed models. Addition of oligomeric and total α-synuclein to the model did not improve the diagnostic power of the biomarker panel. We provide evidence that ER stress-regulated proteins merit further investigation for their potential as diagnostic biomarkers of PD.

Keywords: Biomarker; Chaperone; Endoplasmic reticulum (ER) stress; Parkinson’s disease (PD); Serum

DOI: https://doi.org/10.1007/s12035-022-03139-0

Pol Przegl Chir. 2022 Mar 15. 94(6): 17-25

Small-molecule inhibitors of the PERK-mediated Unfolded Protein Response signaling pathway in targeted therapy for colorectal cancer.

Wioletta Rozpedek-Kaminska, Danuta Piotrzkowska, Grzegorz Galita, Dariusz Pytel, Ewa Kucharska, Łukasz Dziki, Adam Dziki, Ireneusz Majsterek.

Introduction: The newest data has reported that endoplasmic reticulum (ER) stress and PERK-dependent Unfolded Protein Response (UPR) signaling pathway may constitute a key factor in colorectal cancer (CRC) pathogenesis on the molecular level. Nowadays used anti-cancer treatment strategies are still insufficient, since patients suffer from various side effects that are directly evoked via therapeutic agents characterized by non-specific action in normal and cancer cells. Aim: Thereby, the main aim of the presented research was to analyze the effectiveness of the small-molecule PERK inhibitor NCI 12487 in an in vitro cellular model of CRC. Materials and methods: The study was performed on colorectal cancer HT-29 and normal human colon epithelial CCD 841 CoN cell lines. The cytotoxicity was measured by XTT assay, evaluation of apoptosis was performed by caspase-3 assay, whereas cell cycle analysis via the propidium iodide (PI) staining. Results: Results obtained have demonstrated that the investigated compound is selective only for HT-29 cancer cells, since at 25 μM concentration it significantly decreased HT-29 cells viability in a dose- and time-dependent manner, evoked increased caspase-3 activity and arrest in the G2/M phase of the cell cycle. Moreover, NCI 12487 compound markedly decreased HT-29 cells viability, increased caspase-3 activity and percentage of cells in sub-G0/G1, thus promoted apoptosis of cancer HT-29 cells with induced ER stress conditions. Conclusion: Thus, based on the results obtained in this study it may be concluded that small-molecule modulators of the PERK-dependent UPR signaling pathway may constitute an innovative, targeted treatment strategy against CRC.

Keywords: PERK inhibitors; apoptosis; cancer treatment; colorectal cancer; endoplasmic reticulum stress; unfolded protein response

DOI: https://doi.org/10.5604/01.3001.0015.7948

Sci Adv. 2022 Dec 09. 8(49): eabq3970

Glia of C. elegans coordinate a protective organismal heat shock response independent of the neuronal thermosensory circuit.

Holly K Gildea, Phillip A Frankino, Sarah U Tronnes, Corinne L Pender, Jenni Durieux, Julian G Dishart, Hyun Ok Choi, Tayla D Hunter, Shannon S Cheung, Ashley E Frakes, Edward Sukarto, Kevin Wickham, Andrew Dillin.

Aging organisms lose the ability to induce stress responses, becoming vulnerable to protein toxicity and tissue damage. Neurons can signal to peripheral tissues to induce protective organelle-specific stress responses. Recent work shows that glia can independently induce such responses. Here, we show that overexpression of heat shock factor 1 (hsf-1) in the four astrocyte-like cephalic sheath cells of Caenorhabditis elegans induces a non-cell-autonomous cytosolic unfolded protein response, also known as the heat shock response (HSR). These animals have increased lifespan and heat stress resistance and decreased protein aggregation. Glial HSR regulation is independent of canonical thermosensory circuitry and known neurotransmitters but requires the small clear vesicle release protein UNC-13. HSF-1 and the FOXO transcription factor DAF-16 are partially required in peripheral tissues for non-cell-autonomous HSR, longevity, and thermotolerance. Cephalic sheath glial hsf-1 overexpression also leads to pathogen resistance, suggesting a role for this signaling pathway in immune function.

DOI: https://doi.org/10.1126/sciadv.abq3970