scholarly journals SIRT1 Protects the Heart from ER Stress-Induced Injury by Promoting eEF2K/eEF2-Dependent Autophagy

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 426 ◽  
Author(s):  
Julie Pires Da Silva ◽  
Kevin Monceaux ◽  
Arnaud Guilbert ◽  
Mélanie Gressette ◽  
Jérôme Piquereau ◽  
...  

Many recent studies have demonstrated the involvement of endoplasmic reticulum (ER) stress in the development of cardiac diseases and have suggested that modulation of ER stress response could be cardioprotective. Previously, we demonstrated that the deacetylase Sirtuin 1 (SIRT1) attenuates ER stress response and promotes cardiomyocyte survival. Here, we investigated whether and how autophagy plays a role in SIRT1-afforded cardioprotection against ER stress. The results revealed that protective autophagy was initiated before cell death in response to tunicamycin (TN)-induced ER stress in cardiac cells. SIRT1 inhibition decreased ER stress-induced autophagy, whereas its activation enhanced autophagy. In response to TN- or isoproterenol-induced ER stress, mice deficient for SIRT1 exhibited suppressed autophagy along with exacerbated cardiac dysfunction. At the molecular level, we found that in response to ER stress (i) the extinction of eEF2 or its kinase eEF2K not only reduced autophagy but further activated cell death, (ii) inhibition of SIRT1 inhibited the phosphorylation of eEF2, (iii) eIF2α co-immunoprecipitated with eEF2K, and (iv) knockdown of eIF2α reduced the phosphorylation of eEF2. Our results indicate that in response to ER stress, SIRT1 activation promotes cardiomyocyte survival by enhancing autophagy at least through activation of the eEF2K/eEF2 pathway.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 258-258
Author(s):  
Marc S. Raab ◽  
Klaus Podar ◽  
Jing Zhang ◽  
Giovanni Tonon ◽  
Johannes H. Fruehauf ◽  
...  

Abstract We have previously shown that the novel orally available small molecule inhibitor of PKC enzastaurin (Eli Lilly and Company) inhibits MM cell growth, survival and angiogenesis both in vitro and in vivo. To date, however, the downstream effects contributing to growth inhibition and cell death remain to be determined. Here, we performed global gene expression profiling on enzastaurin treated MM cells and identified 200 Genes to be differentially regulated with a > 2-fold cut off. Strikingly, two major groups of up-regulated probe sets were associated with either of two pathways - endoplasmatic reticulum (ER)-stress response or WNT-signaling. Importantly, MM cells, producing high levels of paraprotein, are highly susceptible to perturbation of ER function and protein folding. Moreover, PKC isoforms have been reported to directly regulate the canonical WNT pathway via phosphorylation of b-catenin (CAT), leading to its ubiquination and proteasomal degradation. Specifically, we fist evaluated the role of enzastaurin in mediating ER-stress in MM cells. The transcriptional up-regulation of genes involved in ER-stress (GADD153/CHOP, GADD34, ATF3), triggered by enzastaurin at 3h, was confirmed by western blot analysis, accompanied by induction of the molecular ER chaperone BiP/grp78, phosphorylation of eIF2a consistent with PERK activation, and up-regulation of p21. These events were preceded by an early (1h) increase of intracellular calcium levels, a hallmark of ER-stress, assessed by FLUO4 staining. These data suggest an important role of ER-stress response in the early growth inhibition of MM cells caused by enzastaurin. Second, we delineated effects of enzastaurin on WNT pathway in MM and other tumor cell lines. Upon enzastaurin treatment, CAT was dephosphorylated at Ser33, 37, 41 in a dose- and time-dependent manner in all cell lines tested (10 MM, 3 colon cancer, HeLa, as well as human embryonic kidney 293 cells). Consequently, accumulation of CAT occurred in both cytosolic and nuclear fractions of treated MM cells, associated with activated TOPflash LUC-reporter system, confirming nuclear transactivating activity. Specific inhibition of CAT by siRNA partially rescued HeLa, HEK 293, and MM cells from cell death induced by enzastaurin. Analysis of downstream target molecules revealed a CAT-dependent up-regulation of c-Jun, but not of c-Myc or Cyclin D1. c-Jun has been reported to stabilize p73, a pro-apoptotic p53-family member; CAT induction by enzastaurin led to p73 (but not p53) activation and was also abrogated by CAT-specific siRNA. In turn, specific knockdown of p73 by siRNA rescued cells from enzastaurin-induced apoptosis. Finally, ectopic overexpression of CAT in HeLa and MM cells induced c-Jun expression and p73 activation, followed by apoptotic cell death. Our studies therefore indicate that ER-stress response contributes to the immediate inhibition of proliferation by enzastaurin, followed by CAT accumulation leading to p73 activation, contributing to enzastaurin-mediated cell death. These findings provide a novel link between CAT and p53-family members. Moreover p73, which is only rarely mutated in human cancers, represents a novel therapeutic target in MM.


2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Ken-ichiro Tanaka ◽  
Misato Kasai ◽  
Mikako Shimoda ◽  
Ayane Shimizu ◽  
Maho Kubota ◽  
...  

Trace metals such as zinc (Zn), copper (Cu), and nickel (Ni) play important roles in various physiological functions such as immunity, cell division, and protein synthesis in a wide variety of species. However, excessive amounts of these trace metals cause disorders in various tissues of the central nervous system, respiratory system, and other vital organs. Our previous analysis focusing on neurotoxicity resulting from interactions between Zn and Cu revealed that Cu2+ markedly enhances Zn2+-induced neuronal cell death by activating oxidative stress and the endoplasmic reticulum (ER) stress response. However, neurotoxicity arising from interactions between zinc and metals other than copper has not been examined. Thus, in the current study, we examined the effect of Ni2+ on Zn2+-induced neurotoxicity. Initially, we found that nontoxic concentrations (0–60 μM) of Ni2+ enhance Zn2+-induced neurotoxicity in an immortalized hypothalamic neuronal cell line (GT1-7) in a dose-dependent manner. Next, we analyzed the mechanism enhancing neuronal cell death, focusing on the ER stress response. Our results revealed that Ni2+ treatment significantly primed the Zn2+-induced ER stress response, especially expression of the CCAAT-enhancer-binding protein homologous protein (CHOP). Finally, we examined the effect of carnosine (an endogenous peptide) on Ni2+/Zn2+-induced neurotoxicity and found that carnosine attenuated Ni2+/Zn2+-induced neuronal cell death and ER stress occurring before cell death. Based on our results, Ni2+ treatment significantly enhances Zn2+-induced neuronal cell death by priming the ER stress response. Thus, compounds that decrease the ER stress response, such as carnosine, may be beneficial for neurological diseases.


2011 ◽  
Vol 286 (28) ◽  
pp. 24743-24753 ◽  
Author(s):  
Geum-Hwa Lee ◽  
Do-Sung Kim ◽  
Hyung-Tae Kim ◽  
Jung-Wook Lee ◽  
Chin-Ha Chung ◽  
...  

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Myong-Ho Jeong ◽  
Hyeon-Ju Jeong ◽  
Byeong-Yun Ahn ◽  
Jung-Hoon Pyun ◽  
Ilmin Kwon ◽  
...  

AbstractEndoplasmic reticulum (ER) stress signaling plays a critical role in the control of cell survival or death. Persistent ER stress activates proapoptotic pathway involving the ATF4/CHOP axis. Although accumulating evidences support its important contribution to cardiovascular diseases, but its mechanism is not well characterized. Here, we demonstrate a critical role for PRMT1 in the control of ER stress in cardiomyocytes. The inhibition of PRMT1 augments tunicamycin (TN)-triggered ER stress response in cardiomyocytes while PRMT1 overexpression attenuates it. Consistently, PRMT1 null hearts show exacerbated ER stress and cell death in response to TN treatment. Interestingly, ATF4 depletion attenuates the ER stress response induced by PRMT1 inhibition. The methylation-deficient mutant of ATF4 with the switch of arginine 239 to lysine exacerbates ER stress accompanied by enhanced levels of proapoptotic cleaved Caspase3 and phosphorylated-γH2AX in response to TN. The mechanistic study shows that PRMT1 modulates the protein stability of ATF4 through methylation. Taken together, our data suggest that ATF4 methylation on arginine 239 by PRMT1 is a novel regulatory mechanism for protection of cardiomyocytes from ER stress-induced cell death.


2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A654-A654
Author(s):  
Kerry Klussman ◽  
Elena-Marie Tenn ◽  
Shaylin Higgins ◽  
Rebecca Mazahreh ◽  
Katie Snead ◽  
...  

BackgroundEffective cancer treatment requires durable elimination of malignant cells. Cytotoxic chemotherapeutic agents used to treat cancer often show initial anti-tumor efficacy, but fail to produce long-term durable responses in patients. The elicitation of durable responses and improved survival in response to cytotoxic agents may be associated with the induction of innate and adaptive immune response to the cancer. For example, tumor cells undergoing apoptosis following exposure to some cytotoxic agents emit immunostimulatory damage-associated molecular patterns (DAMPs), this form of cell death is termed immunogenic cell death (ICD). ICD can promote the recruitment and activation of both the innate and adaptive immune system, providing an additional mechanism to drive an anti-tumor response.MethodsVedotin-based antibody drug conjugates (ADCs) drive cytotoxicity in tumor cells by engaging tumor antigens on the cell surface, internalizing with the cell surface antigen, and delivering monomethyl auristatin E (MMAE) payload. Following intracellular delivery, MMAE induces mitotic arrest, as well as an endoplasmic reticulum (ER) stress response resulting from microtubule disruption. Following tumor cell treatment, indicators of the ER stress response are observed with vedotin-based ADCs including induction of phospho-JNK and CHOP, This mechanism of MMAE induced ER stress results in emission of hallmark ICD DAMPs including cell-surface calreticulin, extracellular release of HMGB1 and ATP. In this presentation we highlight the ability of MMAE to induce the hallmarks of ICD in multiple cancers across different tissue origins using distinct valine-citrulline-MMAE (vedotin)-based ADCs.ResultsThe culmination of these ICD hallmarks resulted in innate immune cell activation in vitro and in vivo in mouse xenograft models. Tumor bearing mice treated with vedotin-based ADCs resulted in the promotion of immune cell recruitment and activation in tumors. Analysis of immune activation by vedotin-based ADCs included production of innate cytokines and upregulation of HLA/MHC-Class I/II expression, which supports a role in activating both the innate and adaptive immune response. To further our understanding of the potent and broad ability of vedotin ADCs to induce ICD, we have also begun to examine the ICD potential of different classes of ADC payloads including other microtubule inhibitors (auristatins and maytansines), and DNA damaging agents (DNA alkylators or topoisomerase inhibitors). Initial data indicate differences in ICD induction by these agents.ConclusionsThese results help build the rationale for vedotin-based ADCs as preferred partners for immune checkpoint blockade agents.Ethics ApprovalStudies with human samples were performed according to institutional ethics standards. Animal studies were approved by and conducted in accordance with Seattle Genetics Institutional Care and Use Committee protocol #SGE-029.


Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Mahmood Mozaffari ◽  
Jun Yao Liu ◽  
Babak Baban

An integral component of endoplasmic reticulum (ER) stress-induced apoptosis is expression of growth arrest- and DNA damage inducible protein 153 (GADD153); this protein is normally expressed in low levels but its expression markedly increases following sustained stress to the ER. GADD153 regulates both apoptosis and inflammatory response. We previously showed that pressure overload exacerbates myocardial ischemia reperfusion (IR) injury. In this study, we tested the hypothesis that pressure overload regulates ER stress response manifested as increased GADD153 expression thereby upregulating inflammatory cytokine production and contributing to worsening of myocardial IR injury. Accordingly, Langendorff-perfused rat hearts were subjected to global IR protocol with perfusion pressure set at 80 or 160 cmH 2 O; normoxic hearts served as controls. Compared to normoxia, an IR insult increased expressions of pro-inflammatory cytokine (interleukin (IL)-17) and GADD153 in association with increased cell death. In the ischemic-reperfused hearts, pressure overload a) increased expression of GADD153, b) reduced interleukin (IL)-10 but increased IL-17 and c) increased annexin V immunostaining as well as apoptotic and necrotic cell death. Collectively, the results suggest that pressure overload exacerbates cell death in the isolated ischemic-reperfused heart involving regulation of ER stress response and inflammation.


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