scholarly journals A Novel Therapeutic Strategy for Preferential Elimination of Multiple Myeloma Cells By Targeting Protein Disulfide Isomerase

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Metis Hasipek ◽  
Dale Grabowski ◽  
Yihong Guan ◽  
Anand D. Tiwari ◽  
Xiaorong Gu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Secreted Proteins ◽  
Unfolded Protein ◽  
Protein Response ◽  
Protein Disulfide

Multiple myeloma (MM) is a genetically complex hematological disease which is characterized by clonal proliferation of plasma cells in the bone marrow and secretion of monoclonal antibodies and cytokines that can damage bone, bone marrow, and kidney function1. MM cells constantly operate at the limit of their unfolded protein response (UPR) in the face of a secretory load of immunoglobin (Ig) and cytokines that is unparalleled by any other mammalian cell 2,3 and microenvironmental factors that aggravate the degree of physiologic misfolding that occurs during synthesis of secreted proteins. The endoplasmic reticulum (ER) resident protein disulfide isomerases (PDIs) are indispensable for folding of secreted proteins that require intramolecular disulfide-bond arrangement 4 like antibodies and many cytokines. As the main PDI family member, near-complete function of PDIA1 is essential for survival of MM cells while its inhibition should be manageable by the UPR in normal cells creating an opportunity for a large therapeutic window for PDI inhibitors in MM. Previously, we discovered and characterized an irreversible PDI inhibitor (CCF642) that induced cell death in MM cells at doses that did not affect survival of normal bone marrow cells. However, CCF642 has poor solubility and suboptimal selectivity precluding clinical translation. Using structure guided medicinal chemistry, we developed and characterized a highly potent and selective PDI inhibitor, with 10-fold higher potency (Fig 1B) and selectivity. CCF642-34 showed remarkable selectivity against PDIA1 and off-target bindings were eliminated when compared to CCF642 (Fig 1C). In addition to improved selectivity and in vitro PDI inhibition, CCF642-34 demonstrated more than 3-fold higher potency compared to CCF642 against MM1.S and bortezomib resistant MM1.S cells remained sensitive to CCF642-34. Importantly, the novel analogue CCF642-34 has 18-fold better potency in restricting the colony forming abilities of RPMI1640 cells while at no effect on the clonogenic potential of CD34+ cells derived from healthy bone marrow was observed at equivalent doses. CCF642-34 induces ER stress in MM1.S cells as observed in dose and time dependent cleavage of XBP1, IRE1α oligomerization and the profound induction of programmed cell death reflected by PARP and caspase 3 cleavage. To further analyze the modes of action of CCF642-34 and CCF642 we performed RNAseq after treatment of MM1.S cells and found exclusive induction of genes associated with UPR and downstream cell cycle and apoptotic responses for CCF642-34 while additional genes affecting were detected after CCF642 treatment. There were 362 and 568 differentially expressed genes in CCF642-34 and CCF-642 (compared to controls) treated MM1.S cells, respectively. Among these differentially expressed genes 87 down regulated and 142 upregulated were common to both, including downregulation of cell division and mitotic cell cycle process, and upregulation of response to ER stress, unfolded protein response, and apoptotic process gene sets. Results confirm that both CCF642 and CCF642-34 treatment act by inducing lethal ER-stress with greater selectivity for CCF642-34. Accordingly, hierarchical clustering showed distinct gene expression profiles in 642-34 and 642 treated MM1S cells (Fig. 2). CCF642-34 is orally bioavailable and highly efficacious in against established multiple myeloma in a syngeneic 5TGM1-luc/C57BL/KaLwRij model of myeloma. All vehicle control animals were dead by 52 days while 3 out of 6 mice lived beyond 6 months with no sign of relapse. In summary, we synthesized and characterized a novel lead PDIA1 inhibitor based on structure-guided medicinal chemistry that has improved pharmacologic properties to act as novel lead for clinical translation. References: 1. Manier S, Salem KZ, Park J, et al. Genomic complexity of multiple myeloma and its clinical implications. Nat. Rev. Clin. Oncol. 2017; 2. Fonseca R, Bergsagel PL, Drach J, et al. International Myeloma Working Group molecular classification of multiple myeloma: Spotlight review. Leukemia. 2009; 3. Wang M, Kaufman RJ. The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat. Rev. Cancer. 2014; 4. Freedman RB, Hirst TR, Tuite MF. Protein disulphide isomerase: building bridges in protein folding. Trends Biochem. Sci. 1994; Disclosures Valent: Takeda Pharmaceuticals: Other: Teaching, Speakers Bureau; Celgene: Other: Teaching, Speakers Bureau; Amgen Inc.: Other: Teaching, Speakers Bureau.

scholarly journals A Novel Transcription Factor, ERD15 (Early Responsive to Dehydration 15), Connects Endoplasmic Reticulum Stress with an Osmotic Stress-induced Cell Death Signal

2011 ◽  
Vol 286 (22) ◽  
pp. 20020-20030 ◽  
Author(s):  
Murilo S. Alves ◽  
Pedro A. B. Reis ◽  
Silvana P. Dadalto ◽  
Jerusa A. Q. A. Faria ◽  
Elizabeth P. B. Fontes ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Transcription Factor ◽  
Osmotic Stress ◽  
Er Stress ◽  
Unfolded Protein ◽  
Eukaryotic Organisms ◽  
Protein Response

As in all other eukaryotic organisms, endoplasmic reticulum (ER) stress triggers the evolutionarily conserved unfolded protein response in soybean, but it also communicates with other adaptive signaling responses, such as osmotic stress-induced and ER stress-induced programmed cell death. These two signaling pathways converge at the level of gene transcription to activate an integrated cascade that is mediated by N-rich proteins (NRPs). Here, we describe a novel transcription factor, GmERD15 (Glycine max Early Responsive to Dehydration 15), which is induced by ER stress and osmotic stress to activate the expression of NRP genes. GmERD15 was isolated because of its capacity to stably associate with the NRP-B promoter in yeast. It specifically binds to a 187-bp fragment of the NRP-B promoter in vitro and activates the transcription of a reporter gene in yeast. Furthermore, GmERD15 was found in both the cytoplasm and the nucleus, and a ChIP assay revealed that it binds to the NRP-B promoter in vivo. Expression of GmERD15 in soybean protoplasts activated the NRP-B promoter and induced expression of the NRP-B gene. Collectively, these results support the interpretation that GmERD15 functions as an upstream component of stress-induced NRP-B-mediated signaling to connect stress in the ER to an osmotic stress-induced cell death signal.

scholarly journals Human Cytomegalovirus Protein pUL38 Induces ATF4 Expression, Inhibits Persistent JNK Phosphorylation, and Suppresses Endoplasmic Reticulum Stress-Induced Cell Death

2009 ◽  
Vol 83 (8) ◽  
pp. 3463-3474 ◽  
Author(s):  
Baoqin Xuan ◽  
Zhikang Qian ◽  
Emi Torigoi ◽  
Dong Yu
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Human Cytomegalovirus ◽  
Initiation Factor ◽  
Α Subunit ◽  
Unfolded Protein ◽  
Initiation Factor 2 ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT The endoplasmic reticulum (ER) is a key organelle involved in sensing and responding to stressful conditions, including those resulting from infection of viruses, such as human cytomegalovirus (HCMV). Three signaling pathways collectively termed the unfolded protein response (UPR) are activated to resolve ER stress, but they will also lead to cell death if the stress cannot be alleviated. HCMV is able to modulate the UPR to promote its infection. The specific viral factors involved in such HCMV-mediated modulation, however, were unknown. We previously showed that HCMV protein pUL38 was required to maintain the viability of infected cells, and it blocked cell death induced by thapsigargin. Here, we report that pUL38 is an HCMV-encoded regulator to modulate the UPR. In infection, pUL38 allowed HCMV to upregulate phosphorylation of PKR-like ER kinase (PERK) and the α subunit of eukaryotic initiation factor 2 (eIF-2α), as well as induce robust accumulation of activating transcriptional factor 4 (ATF4), key components of the PERK pathway. pUL38 also allowed the virus to suppress persistent phosphorylation of c-Jun N-terminal kinase (JNK), which was induced by the inositol-requiring enzyme 1 pathway. In isolation, pUL38 overexpression elevated eIF-2α phosphorylation, induced ATF4 accumulation, limited JNK phosphorylation, and suppressed cell death induced by both thapsigargin and tunicamycin, two drugs that induce ER stress by different mechanisms. Importantly, ATF4 overexpression and JNK inhibition significantly reduced cell death in pUL38-deficient virus infection. Thus, pUL38 targets ATF4 expression and JNK activation, and this activity appears to be critical for protecting cells from ER stress induced by HCMV infection.

Modulation of ER Stress/Unfolded Protein Response (UPR) Pathways in Multiple Myeloma Cells by Inhibition of Hsp90 and Serine-Threonine Kinase CK2.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3840-3840
Author(s):  
Francesco Piazza ◽  
Sabrina Manni ◽  
Carmela Gurrieri ◽  
Anna Colpo ◽  
Laura Quotti Tubi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Hsp90 Inhibitors ◽  
Hsp90 Inhibition ◽  
Protein Levels ◽  
Unfolded Protein ◽  
Protein Response ◽  
Kinase Ck2

Abstract Abstract 3840 Poster Board III-776 Hsp90 is an essential chaperone molecule that helps in the maturation and folding of a number of cellular client proteins. Hsp90 function is essential for malignant plasma cell survival, since its inhibition in multiple myeloma (MM) cells results in cell death and activation of apoptosis. Clinical trials using Hsp90 inhibitors are currently ongoing in MM patients. Hsp90 inactivation in MM cells causes perturbation of the endoplasmic reticulum (ER) stress/unfolded protein response (UPR), eventually triggering the apoptotic cascades. Protein kinase CK2 critically regulates the activity of the chaperone complex formed by the Cdc37 and Hsp90 proteins. We already described that CK2 is over-expressed in a fraction of MM patients and is an essential MM pro-survival molecule. We have here investigated its role in the ER stress/UPR pathways and in Hsp90 inhibition-induced apoptosis in MM cells. Down-regulation of the catalytic CK2 alpha subunit with selective chemical inhibitors or RNA interference resulted in significant modifications of the main UPR regulating signaling cascades: 1) a marked reduction of IRE1alpha protein levels; 2) a reduction of BiP/GRP78 and Hsp70 chaperone protein levels; 3) an increase of PERK activity and phospho eIF2alpha levels. When UPR was triggered by thapsigargin in CK2-inactivated cells, we observed that the IRE1alpha-dependent axis of the UPR was greatly impaired, as XBP-1short isoform generation and the levels of some induced chaperones were reduced. Interestingly, thapsigargin was able to induce CK2 kinase activity. Remarkably, treatment of CK2-silenced MM cells with Hsp90 inhibitors geldanamycin or its derivative 17-AAG (17-(demethoxy)-17-allylamino geldanamycin) resulted in 1) an even more pronounced reduction of IRE1 alpha protein levels; 2) a marked inhibition of GA or 17-AAG-triggered BiP/GRP78 protein level raise; 3) a more evident increase of eIF2 alpha phosphorylation. Of note, CK2 plus Hsp90 inhibition was followed by apoptotic cell death to a much greater extent than that obtained with the single inhibition of the two molecules. Noteworthy, these effects were also reproduced upon modelling the MM bone marrow (BM) microenvironment by co-culturing MM cells with BM stromal cells. These data suggest that CK2-mediated signaling regulates the ER stress/UPR pathways and modulates the threshold to apoptosis of ER stressed MM cells. CK2 interacts with Hsp90, since its inhibition synergizes with GA or 17-AAG treatments in terms of induction of apoptosis and shift of the ER stress/UPR pathways towards the terminal phase. These results might be useful to set the groundwork in designing novel combination treatments for MM patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Regulation of podocyte survival and endoplasmic reticulum stress by fatty acids

2010 ◽  
Vol 299 (4) ◽  
pp. F821-F829 ◽  
Author(s):  
Jonas Sieber ◽  
Maja Tamara Lindenmeyer ◽  
Kapil Kampe ◽  
Kirk Nicholas Campbell ◽  
Clemens David Cohen ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Oleic Acid ◽  
Palmitic Acid ◽  
Er Stress ◽  
Unfolded Protein ◽  
Homologous Protein ◽  
Protein Response ◽  
Apoptosis And Necrosis

Apoptosis of podocytes is considered critical in the pathogenesis of diabetic nephropathy (DN). Free fatty acids (FFAs) are critically involved in the pathogenesis of diabetes mellitus type 2, in particular the regulation of pancreatic β cell survival. The objectives of this study were to elucidate the role of palmitic acid, palmitoleic, and oleic acid in the regulation of podocyte cell death and endoplasmic reticulum (ER) stress. We show that palmitic acid increases podocyte cell death, both apoptosis and necrosis of podocytes, in a dose and time-dependent fashion. Palmitic acid induces podocyte ER stress, leading to an unfolded protein response as reflected by the induction of the ER chaperone immunoglobulin heavy chain binding protein (BiP) and proapoptotic C/EBP homologous protein (CHOP) transcription factor. Of note, the monounsaturated palmitoleic and oleic acid can attenuate the palmitic acid-induced upregulation of CHOP, thereby preventing cell death. Similarly, gene silencing of CHOP protects against palmitic acid-induced podocyte apoptosis. Our results offer a rationale for interventional studies aimed at testing whether dietary shifting of the FFA balance toward unsaturated FFAs can delay the progression of DN.

scholarly journals Translational and posttranslational regulation of XIAP by eIF2α and ATF4 promotes ER stress–induced cell death during the unfolded protein response

2014 ◽  
Vol 25 (9) ◽  
pp. 1411-1420 ◽  
Author(s):  
Nobuhiko Hiramatsu ◽  
Carissa Messah ◽  
Jaeseok Han ◽  
Matthew M. LaVail ◽  
Randal J. Kaufman ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Protein Misfolding ◽  
Down Regulation ◽  
Unfolded Protein ◽  
Activity Loss ◽  
The Unfolded Protein Response ◽  
Protein Response

Endoplasmic reticulum (ER) protein misfolding activates the unfolded protein response (UPR) to help cells cope with ER stress. If ER homeostasis is not restored, UPR promotes cell death. The mechanisms of UPR-mediated cell death are poorly understood. The PKR-like endoplasmic reticulum kinase (PERK) arm of the UPR is implicated in ER stress–induced cell death, in part through up-regulation of proapoptotic CCAAT/enhancer binding protein homologous protein (CHOP). Chop−/− cells are partially resistant to ER stress–induced cell death, and CHOP overexpression alone does not induce cell death. These findings suggest that additional mechanisms regulate cell death downstream of PERK. Here we find dramatic suppression of antiapoptosis XIAP proteins in response to chronic ER stress. We find that PERK down-regulates XIAP synthesis through eIF2α and promotes XIAP degradation through ATF4. Of interest, PERK's down-regulation of XIAP occurs independently of CHOP activity. Loss of XIAP leads to increased cell death, whereas XIAP overexpression significantly enhances resistance to ER stress–induced cell death, even in the absence of CHOP. Our findings define a novel signaling circuit between PERK and XIAP that operates in parallel with PERK to CHOP induction to influence cell survival during ER stress. We propose a “two-hit” model of ER stress–induced cell death involving concomitant CHOP up-regulation and XIAP down-regulation both induced by PERK.

scholarly journals Calnexin Is Involved in Apoptosis Induced by Endoplasmic Reticulum Stress in the Fission Yeast

2008 ◽  
Vol 19 (10) ◽  
pp. 4404-4420 ◽  
Author(s):  
Renée Guérin ◽  
Geneviève Arseneault ◽  
Stéphane Dumont ◽  
Luis A. Rokeach
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Er Stress ◽  
Transmembrane Domain ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Apoptotic Death ◽  
Apoptosis Markers ◽  
The Unfolded Protein Response ◽  
Protein Response

Stress conditions affecting the functions of the endoplasmic reticulum (ER) cause the accumulation of unfolded proteins. ER stress is counteracted by the unfolded-protein response (UPR). However, under prolonged stress the UPR initiates a proapoptotic response. Mounting evidence indicate that the ER chaperone calnexin is involved in apoptosis caused by ER stress. Here, we report that overexpression of calnexin in Schizosaccharomyces pombe induces cell death with apoptosis markers. Cell death was partially dependent on the Ire1p ER-stress transducer. Apoptotic death caused by calnexin overexpression required its transmembrane domain (TM), and involved sequences on either side of the ER membrane. Apoptotic death caused by tunicamycin was dramatically reduced in a strain expressing endogenous levels of calnexin lacking its TM and cytosolic tail. This demonstrates the involvement of calnexin in apoptosis triggered by ER stress. A genetic screen identified the S. pombe homologue of the human antiapoptotic protein HMGB1 as a suppressor of apoptotic death due to calnexin overexpression. Remarkably, overexpression of human calnexin in S. pombe also provoked apoptotic death. Our results argue for the conservation of the role of calnexin in apoptosis triggered by ER stress, and validate S. pombe as a model to elucidate the mechanisms of calnexin-mediated cell death.

scholarly journals Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Jennifer L Mamrosh ◽  
Jae Man Lee ◽  
Martin Wagner ◽  
Peter J Stambrook ◽  
Richard J Whitby ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Transcription Factor ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Nuclear Receptor ◽  
Stress Resistance ◽  
Unfolded Protein ◽  
Human Disorders ◽  
Protein Response

Chronic endoplasmic reticulum (ER) stress results in toxicity that contributes to multiple human disorders. We report a stress resolution pathway initiated by the nuclear receptor LRH-1 that is independent of known unfolded protein response (UPR) pathways. Like mice lacking primary UPR components, hepatic Lrh-1-null mice cannot resolve ER stress, despite a functional UPR. In response to ER stress, LRH-1 induces expression of the kinase Plk3, which phosphorylates and activates the transcription factor ATF2. Plk3-null mice also cannot resolve ER stress, and restoring Plk3 expression in Lrh-1-null cells rescues ER stress resolution. Reduced or heightened ATF2 activity also sensitizes or desensitizes cells to ER stress, respectively. LRH-1 agonist treatment increases ER stress resistance and decreases cell death. We conclude that LRH-1 initiates a novel pathway of ER stress resolution that is independent of the UPR, yet equivalently required. Targeting LRH-1 may be beneficial in human disorders associated with chronic ER stress.

scholarly journals The Emerging Role of Electrophiles as a Key Regulator for Endoplasmic Reticulum (ER) Stress

2019 ◽  
Vol 20 (7) ◽  
pp. 1783 ◽  
Author(s):  
Takasugi ◽  
Hiraoka ◽  
Nakahara ◽  
Akiyama ◽  
Fujikawa ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Stress Sensors ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Protein Disulfide ◽  
The Relationship

The unfolded protein response (UPR) is activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER), which is called ER stress. ER stress sensors PERK, IRE1, and ATF6 play a central role in the initiation and regulation of the UPR; they inhibit novel protein synthesis and upregulate ER chaperones, such as protein disulfide isomerase, to remove unfolded proteins. However, when recovery from ER stress is difficult, the UPR pathway is activated to eliminate unhealthy cells. This signaling transition is the key event of many human diseases. However, the precise mechanisms are largely unknown. Intriguingly, reactive electrophilic species (RES), which exist in the environment or are produced through cellular metabolism, have been identified as a key player of this transition. In this review, we focused on the function of representative RES: nitric oxide (NO) as a gaseous RES, 4-hydroxynonenal (HNE) as a lipid RES, and methylmercury (MeHg) as an environmental organic compound RES, to outline the relationship between ER stress and RES. Modulation by RES might be a target for the development of next-generation therapy for ER stress-associated diseases.

scholarly journals PERK Signaling Regulates Extracellular Proteostasis of an Amyloidogenic Protein During Endoplasmic Reticulum Stress

2018 ◽  
Author(s):  
Isabelle C. Romine ◽  
R. Luke Wiseman
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Secreted Proteins ◽  
Unfolded Protein ◽  
Er Retention ◽  
Amyloidogenic Protein ◽  
The Unfolded Protein Response ◽  
Stress Dependent ◽  
Protein Response ◽  
The Impact

ABSTRACTThe PERK arm of the unfolded protein response (UPR) regulates cellular proteostasis and survival in response to endoplasmic reticulum (ER) stress. However, the impact of PERK signaling on extracellular proteostasis is poorly understood. We define how PERK signaling influences extracellular proteostasis during ER stress using a conformational reporter of the secreted amyloidogenic protein transthyretin (TTR). We show that inhibiting PERK signaling impairs ER stress-dependent secretion of destabilized TTR by increasing its ER retention in chaperone-bound complexes. Interestingly, PERK inhibition promotes the ER stress-dependent secretion of TTR in non-native conformations that accumulate extracellularly as soluble oligomers. Pharmacologic or genetic TTR stabilization partially restores secretion of native TTR tetramers. However, PERK inhibition still increases the ER stress-dependent secretion of TTR in non-native conformations under these conditions, indicating that the conformation of stable secreted proteins can also be affected by inhibiting PERK. Our results define a role for PERK in regulating extracellular proteostasis during ER stress and indicate that genetic or aging-related alterations in PERK signaling can exacerbate ER stress-related imbalances in extracellular proteostasis implicated in diverse diseases.

scholarly journals Reduced endoplasmic reticulum stress-induced apoptosis and impaired unfolded protein response in TRPC3-deficient M1 macrophages

2014 ◽  
Vol 307 (6) ◽  
pp. C521-C531 ◽  
Author(s):  
Sumeet Solanki ◽  
Prabhatchandra R. Dube ◽  
Jean-Yves Tano ◽  
Lutz Birnbaumer ◽  
Guillermo Vazquez
Keyword(s):  
Bone Marrow ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Unfolded Protein ◽  
Macrophage Apoptosis ◽  
Induced Apoptosis ◽  
Protein Response

Endoplasmic reticulum (ER) stress is a prominent mechanism of macrophage apoptosis in advanced atherosclerotic lesions. Recent studies from our laboratory showed that advanced atherosclerotic plaques in Apoe−/− mice with bone marrow deficiency of the calcium-permeable channel Transient Receptor Potential Canonical 3 (TRPC3) are characterized by reduced areas of necrosis and fewer apoptotic macrophages than animals transplanted with Trpc3+/+ bone marrow. In vitro, proinflammatory M1 but not anti-inflammatory M2 macrophages derived from Trpc3−/−Apoe−/− animals exhibited reduced ER stress-induced apoptosis. However, whether this was due to a specific effect of TRPC3 deficiency on macrophage ER stress signaling remained to be determined. In the present work we used polarized macrophages derived from mice with macrophage-specific deficiency of TRPC3 to examine the expression level of ER stress markers and the activation status of some typical mediators of macrophage apoptosis. We found that the reduced susceptibility of TRPC3-deficient M1 macrophages to ER stress-induced apoptosis correlates with an impaired unfolded protein response (UPR), reduced mitochondrion-dependent apoptosis, and reduced activation of the proapoptotic molecules calmodulin-dependent protein kinase II and signal transducer and activator of transcription 1. Notably, none of these pathways was altered in TRPC3-deficient M2 macrophages. These findings show for the first time an obligatory requirement for a member of the TRPC family of cation channels in ER stress-induced apoptosis in macrophages, underscoring a rather selective role of the TRPC3 channel on mechanisms related to the UPR signaling in M1 macrophages.

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