Trichoderma reesei prs12 encodes a stress- and unfolded-protein-response-inducible regulatory subunit of the fungal 26S proteasome

1998 ◽  
Vol 33 (4) ◽  
pp. 284-290 ◽  
Author(s):  
Sabine P. Goller ◽  
Markus Gorfer ◽  
C. P. Kubicek
Keyword(s):  
Unfolded Protein Response ◽  
Trichoderma Reesei ◽  
26S Proteasome ◽  
Regulatory Subunit ◽  
Unfolded Protein ◽  
Protein Response

scholarly journals Induction of gut proteasome activity in hemorrhagic shock and its recovery by treatment with diphenyldihaloketones CLEFMA and EF24

2018 ◽  
Vol 315 (2) ◽  
pp. G318-G327 ◽  
Author(s):  
Geeta Rao ◽  
Hailey Houson ◽  
Gregory Nkepang ◽  
Hooman Yari ◽  
Chengwen Teng ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Hemorrhagic Shock ◽  
Unfolded Protein Response ◽  
Systemic Inflammatory Response ◽  
Proteasome Activity ◽  
26S Proteasome ◽  
Barrier Dysfunction ◽  
Gut Barrier ◽  
Unfolded Protein ◽  
Protein Response

Multiorgan failure in hemorrhagic shock is triggered by gut barrier dysfunction and consequent systemic infiltration of proinflammatory factors. Our previous study has shown that diphenyldihaloketone drugs 4-[3,5-bis[(2-chlorophenyl)methylene]-4-oxo-1-piperidinyl]-4-oxo-2-butenoic acid (CLEFMA) and 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone (EF24) restore gut barrier dysfunction and reduce systemic inflammatory response in hemorrhagic shock. We investigated the effect of hemorrhagic shock on proteasome activity of intestinal epithelium and how CLEFMA and EF24 treatments modulate proteasome function in hemorrhagic shock. CLEFMA or EF24 (0.4 mg/kg) were given 1 h after withdrawing 50% of blood from Sprague-Dawley rats; no other resuscitation was provided. After another 5 h of compensation, small gut was collected to process tissue for proteasome activity, immunoblotting, and mRNA levels of genes responsible for unfolded-protein response (XBP1, ATF4, glucose-regulated protein of 78/95 kDa, and growth arrest and DNA damage inducible genes 153/34), polyubiquitin B and C, and immunoproteasome subunits β type-8 and -10 and proteasome activator subunit 1. We found that hemorrhagic shock induced proteasome activity in gut tissue and reduced the amounts of ubiquitinated proteins displayed on antiubiquitin immunoblots. However, simultaneous induction of unfolded-protein response or immunoproteasome genes was not observed. CLEFMA and EF24 treatments abolished the hemorrhagic shock-induced increase in proteasome activity. Further investigations revealed that the induction of proteasome in hemorrhagic shock is associated with disassembly of 26S proteasome; CLEFMA and EF24 prevented this disassembly. Consistent with these data, CLEFMA and EF24 reduced hemorrhagic shock-induced degradation of 20S substrate ornithine decarboxylase in gut tissue. These results suggest that activated proteasome plays an important role in ischemic gut pathophysiology, and it can be a druggable target in shock-induced gut dysfunction. NEW & NOTEWORTHY Ischemic injury to the gut is a trigger for the systemic inflammatory response and multiple organ failure in trauma and hemorrhagic shock. We show for the first time that hemorrhagic shock induces the gut proteasome activity by engendering 26S proteasome disassembly. Diphenyldihaloketones 4-[3,5-bis[(2-chlorophenyl)methylene]-4-oxo-1-piperidinyl]-4-oxo-2-butenoic acid and 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone treatment prevented the 26S disassembly. Understanding the role of proteasome in shock-associated gut injury will assist in the development of therapeutic means to address it.

scholarly journals HY5, a positive regulator of light signaling, negatively controls the unfolded protein response inArabidopsis

2017 ◽  
Vol 114 (8) ◽  
pp. 2084-2089 ◽  
Author(s):  
Ganesh M. Nawkar ◽  
Chang Ho Kang ◽  
Punyakishore Maibam ◽  
Joung Hun Park ◽  
Young Jun Jung ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Molecular Mechanism ◽  
26S Proteasome ◽  
Light Signaling ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
The Unfolded Protein Response ◽  
Protein Response

Light influences essentially all aspects of plant growth and development. Integration of light signaling with different stress response results in improvement of plant survival rates in ever changing environmental conditions. Diverse environmental stresses affect the protein-folding capacity of the endoplasmic reticulum (ER), thus evoking ER stress in plants. Consequently, the unfolded protein response (UPR), in which a set of molecular chaperones is expressed, is initiated in the ER to alleviate this stress. Although its underlying molecular mechanism remains unknown, light is believed to be required for the ER stress response. In this study, we demonstrate that increasing light intensity elevates the ER stress sensitivity of plants. Moreover, mutation of the ELONGATED HYPOCOTYL 5 (HY5), a key component of light signaling, leads to tolerance to ER stress. This enhanced tolerance ofhy5plants can be attributed to higher expression of UPR genes. HY5 negatively regulates the UPR by competing with basic leucine zipper 28 (bZIP28) to bind to the G-box–like element present in the ER stress response element (ERSE). Furthermore, we found that HY5 undergoes 26S proteasome-mediated degradation under ER stress conditions. Conclusively, we propose a molecular mechanism of crosstalk between the UPR and light signaling, mediated by HY5, which positively mediates light signaling, but negatively regulates UPR gene expression.

XBP-1 Levels Predict Sensitivity of Myelomas to Proteasome Inhibitor Bortezomib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1473-1473
Author(s):  
Silvia C. Ling ◽  
Edwin Lau ◽  
Lye L. Ho ◽  
Joy Ho ◽  
Douglas E. Joshua ◽  
...  
Keyword(s):  
Unfolded Protein Response ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Myeloma Cell ◽  
26S Proteasome ◽  
Mrna Levels ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Background: Proteasome inhibitors (PI) are remarkably effective in relapsed and refractory myeloma but the origin of this peculiar sensitivity remains unclear. Myeloma is dependent on the unfolded protein response (UPR) and its regulator, transcription factor XBP-1. PI perturbs the unfolded protein response (UPR) by inhibition of the 26S proteasome-the main pathway for protein degradation. We hypothesize that the dependence on the UPR and XBP-1 mediates sensitivity to PI and the level of XBP-1 correlates with sensitivity to PI. The aim of this study is to correlate Bortezomib sensitivity with XBP-1 in vitro and in myeloma patients; to check the effect of manipulating XBP-1 on Bortezomib sensitivity and develop Bortezomib-resistant myeloma cell lines to ascertain the effects on XBP-1 and the UPR. Methods and Results: Sensitivity to Bortezomib was measured by growth inhibition assay. XBP-1 mRNA levels and its isoforms were measured by a two-step quantitative QPCR assay, in 6 myeloma cell lines and 17 other cancer cell lines. There is a strong inverse correlation in myeloma cell lines between total or unspliced XBP-1 with Bortezomib sensitivity (r = −0.9) but not in other cancer cell lines. 23 marrow biopsies from 11 Bortezomib-treated myeloma patients were analysed for XBP-1 expression. Myeloma cells (CD38 hi, CD14 lo, kappa or lambda light chain +ve) were purified by flow cytometry. XBP-1 levels in myeloma cell lines were manipulated by shRNA-mediated knockdown and overexpression by retroviral transduction and had little effect on Bortezomib sensitivity. Bortezomib-resistant myeloma lines were developed. The mechanism of resistance was elucidated (XBP-1, ATF6, P-EIF2a, P58 INK and immunogloblin production). Marked downregulation of XBP-1 was demonstrated. Conclusion: XBP-1 is a surrogate marker of Bortezomib sensitivity and its clinical utility is being tested now. Sensitivity to PI is related to the dependence on the UPR, reflected in the level of XBP-1. Bortezomib resistance is mediated by downregulation of the UPR.

scholarly journals A regulatory subunit of phosphoinositide 3-kinase increases the nuclear accumulation of X-box–binding protein-1 to modulate the unfolded protein response

2010 ◽  
Vol 16 (4) ◽  
pp. 438-445 ◽  
Author(s):  
Jonathon N Winnay ◽  
Jeremie Boucher ◽  
Marcelo A Mori ◽  
Kohjiro Ueki ◽  
C Ronald Kahn
Keyword(s):  
Unfolded Protein Response ◽  
Binding Protein ◽  
Nuclear Accumulation ◽  
Regulatory Subunit ◽  
Unfolded Protein ◽  
Phosphoinositide 3 Kinase ◽  
The Unfolded Protein Response ◽  
Protein Response

scholarly journals Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4907-4916 ◽  
Author(s):  
Esther A. Obeng ◽  
Louise M. Carlson ◽  
Delia M. Gutman ◽  
William J. Harrington ◽  
Kelvin P. Lee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Proteasome Inhibitors ◽  
26S Proteasome ◽  
Secretory Cells ◽  
B Cell Differentiation ◽  
Unfolded Protein ◽  
Induced Apoptosis ◽  
Protein Response

AbstractMultiple myeloma (MM) is an incurable plasma cell malignancy. The 26S proteasome inhibitor, bortezomib, selectively induces apoptosis in MM cells; however, the nature of its selectivity remains unknown. Here we demonstrate that 5 different MM cell lines display similar patterns of sensitivity to 3 proteasome inhibitors (PIs) but respond differently to specific NF-κB inhibition. We further show that PIs initiate the unfolded protein response (UPR), a signaling pathway activated by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). Consistent with reports that prosurvival/physiologic UPR components are required for B-cell differentiation into antibody-secreting cells, we found that MM cells inherently expressed the ER chaperones GRP78/Bip and GRP94/gp96. However, bortezomib rapidly induced components of the proapoptotic/terminal UPR, including PERK, the ER stress–specific eIF-2α kinase; ATF4, an ER stress–induced transcription factor; and its proapoptotic target, CHOP/GADD153. Consistent with our hypothesis that PIs induce the accumulation of misfolded ER-processed proteins, we found that the amount of immunoglobulin subunits retained within MM cells correlated with their sensitivity to PIs. These findings suggest that MM cells have a lower threshold for PI-induced UPR induction and ER stress–induced apoptosis because they constitutively express ER stress survival factors to function as secretory cells.

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