bims-unfpre 2024-05-26 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2024‒05‒26
twelve papers selected by
Susan Logue, University of Manitoba

Kaempferol attenuates particle-induced osteogenic impairment by regulating ER stress via the IRE1α/XBP1s pathway.
Deletion of IRE1α in podocytes exacerbates diabetic nephropathy in mice.
Endoplasmic Reticulum Stress Induced Senescence in Human Lung Fibroblasts.
ENDOPLASMIC RETICULUM: Monitoring and maintaining protein and membrane homeostasis in the endoplasmic reticulum by the unfolded protein response.
p20BAP31 Induces Autophagy in Colorectal Cancer Cells by Promoting PERK-Mediated ER Stress.
FLT3-ITD regulation of the endoplasmic reticulum functions in acute myeloid leukemia.
An Overview of the Unfolded Protein Response (UPR) and Autophagy Pathways in Human Viral Oncogenesis.
Mycoplasma glycine cleavage system key subunit GcvH is an apoptosis inhibitor targeting host endoplasmic reticulum.
LC3A-mediated autophagy elicits PERK-eIF2α-ATF4 axis activation and mitochondrial dysfunction: Exposing vulnerability in aggresome positive cancer cells.
Upregulation of neuronal ER-phagy improves organismal fitness and alleviates APP toxicity.
Activation of the sigma-1 receptor ameliorates neuronal ferroptosis via IRE1α after spinal cord injury.
Mitigation of ROS-triggered endoplasmic reticulum stress by upregulating Nrf2 retards diabetic nephropathy.

J Biol Chem. 2024 May 18. pii: S0021-9258(24)01895-7. [Epub ahead of print] 107394

Kaempferol attenuates particle-induced osteogenic impairment by regulating ER stress via the IRE1α/XBP1s pathway.

Xin Yu, Zhengrong Ren, Yuxiang Wang, Guodong Yuan, Jianlun Hu, Lin Song, Cheng Pan, Kangkang Feng, Yuqiao Liu, Longgang Shao, Li Zhang, Jinjuan Wang, Jianning Zhao, Nirong Bao, Zhongyang Sun.

  Periprosthetic osteolysis and subsequent aseptic loosening are the primary causes of failure following total joint arthroplasty. Wear particle-induced osteogenic impairment is recognized as an important contributing factor in the development of osteolysis, with endoplasmic reticulum (ER) stress emerging as a pivotal underlying mechanism. Hence, searching for potential therapeutic targets and agents capable of modulating ER stress in osteoblasts is crucial for preventing aseptic loosening. Kaempferol (KAE), a natural flavonol compound, has shown promising osteoprotective effects and anti-ER stress properties in diverse diseases. However, the influence of KAE on ER stress-mediated osteogenic impairment induced by wear particles remains unclear. In this study, we observed that KAE effectively relieved TiAl6V4 particles (TiPs)-induced osteolysis by improving osteogenesis in a mouse calvarial model. Furthermore, we demonstrated that KAE could attenuate ER stress-mediated apoptosis in osteoblasts exposed to TiPs, both in vitro and in vivo. Mechanistically, our results revealed that KAE mitigated ER stress-mediated apoptosis by upregulating the IRE1α/XBP1s pathway while concurrently partially inhibiting the IRE1α-regulated RIDD and JNK activation. Collectively, our findings suggest that KAE is a prospective therapeutic agent for treating wear particle-induced osteolysis, and highlight the IRE1α/XBP1s pathway as a potential therapeutic target for preventing aseptic loosening.

Keywords:  Aseptic loosening; ER stress; IRE1α/XBP1s; Kaempferol; Osteoblast; Osteolysis

DOI:  https://doi.org/10.1016/j.jbc.2024.107394
Sci Rep. 2024 05 22. 14(1): 11718

Deletion of IRE1α in podocytes exacerbates diabetic nephropathy in mice.

Andrey V Cybulsky, Joan Papillon, Julie Guillemette, José R Navarro-Betancourt, Chen-Fang Chung, Takao Iwawaki, I George Fantus.

  Protein misfolding in the endoplasmic reticulum (ER) of podocytes contributes to the pathogenesis of glomerular diseases. Protein misfolding activates the unfolded protein response (UPR), a compensatory signaling network. We address the role of the UPR and the UPR transducer, inositol-requiring enzyme 1α (IRE1α), in streptozotocin-induced diabetic nephropathy in mice. Diabetes caused progressive albuminuria in control mice that was exacerbated in podocyte-specific IRE1α knockout (KO) mice. Compared to diabetic controls, diabetic IRE1α KO mice showed reductions in podocyte number and synaptopodin. Glomerular ultrastructure was altered only in diabetic IRE1α KO mice; the major changes included widening of podocyte foot processes and glomerular basement membrane. Activation of the UPR and autophagy was evident in diabetic control, but not diabetic IRE1α KO mice. Analysis of human glomerular gene expression in the JuCKD-Glom database demonstrated induction of genes associated with the ER, UPR and autophagy in diabetic nephropathy. Thus, mice with podocyte-specific deletion of IRE1α demonstrate more severe diabetic nephropathy and attenuation of the glomerular UPR and autophagy, implying a protective effect of IRE1α. These results are consistent with data in human diabetic nephropathy and highlight the potential for therapeutically targeting these pathways.

Keywords:  Albuminuria; Autophagy; Endoplasmic reticulum; Gene expression; Glomerulopathy; Unfolded protein response

DOI:  https://doi.org/10.1038/s41598-024-62599-7
Am J Physiol Lung Cell Mol Physiol. 2024 May 21.

Endoplasmic Reticulum Stress Induced Senescence in Human Lung Fibroblasts.

Maunick Lefin Koloko Ngassie, Li Y Drake, Benjamin B Roos, Amanda Koenig-Kappes, Christina M Pabelick, Reinoud Gosens, Corry-Anke Brandsma, Janette K Burgess, Y S Prakash.

  Loss of proteostasis and cellular senescence have been previously established as characteristics of aging, however their interaction in the context of lung aging and potential contributions to aging-associated lung remodeling remains understudied. In this study we aimed to characterize endoplasmic reticulum (ER) stress response, cellular senescence, and their interaction in relation to extracellular matrix (ECM) production in lung fibroblasts from young (25-45 years) and old (>60 years) humans. Fibroblasts from young and old patients without significant preexisting lung disease were exposed to vehicle, MG132, etoposide or salubrinal. Afterwards, cells and cell lysates or supernatants were analyzed for ER stress, cellular senescence and ECM changes using protein analysis, proliferation assay and senescence-associated beta galactosidase (SA-β-Gal) staining. At baseline, fibroblasts from aging individuals showed increased levels of ER stress (ATF6 and PERK), senescence (p21 and McL-1) and ECM marker (COL1A1) compared to those from young individuals. Upon ER stress induction and etoposide exposure, fibroblasts showed an increase in senescence (SA-β-Gal, p21, Cav-1), ER stress (PERK) and ECM markers (COL1A1 and LUM) compared to vehicle. Additionally, CXCL8 and IL-6 levels were increase in the supernatants of MG132 and etoposide-treated fibroblasts, respectively. Finally, the ER stress inhibitor salubrinal decreased the expression of p21 compared to vehicle and MG132 treatments, however salubrinal inhibited COL1A1 but not p21 expression in MG132-treated fibroblasts. Our study suggests that ER stress response plays an important role in establishment and maintenance of a senescence phenotype in lung fibroblasts and therefore contributes to altered remodeling in the aging lung.

Keywords:  Aging; Extracellular Matrix; Loss of Proteostasis; Lung; Remodeling

DOI:  https://doi.org/10.1152/ajplung.00264.2023
Int J Biochem Cell Biol. 2024 May 18. pii: S1357-2725(24)00090-6. [Epub ahead of print] 106598

ENDOPLASMIC RETICULUM: Monitoring and maintaining protein and membrane homeostasis in the endoplasmic reticulum by the unfolded protein response.

Paulina Kettel, G Elif Karagöz.

  The endoplasmic reticulum (ER) regulates essential cellular processes, including protein folding, lipid synthesis, and calcium homeostasis. The ER homeostasis is maintained by a conserved set of signaling cascades called the Unfolded Protein Response (UPR). How the UPR senses perturbations in ER homeostasis has been the subject of active research for decades. In metazoans, the UPR consists of three ER-membrane embedded sensors: IRE1, PERK and ATF6. These sensors detect the accumulation of misfolded proteins in the ER lumen and adjust protein folding capacity according to cellular needs. Early work revealed that the ER-resident chaperone BiP binds to all three UPR sensors in higher eukaryotes and BiP binding was suggested to regulate their activity. More recent data have shown that in higher eukaryotes the interaction of the UPR sensors with a complex network of chaperones and misfolded proteins modulates their activation and deactivation dynamics. Furthermore, emerging evidence suggests that the UPR monitors ER membrane integrity beyond protein folding defects. However, the mechanistic and structural basis of UPR activation by proteotoxic and lipid bilayer stress in higher eukaryotes remains only partially understood. Here, we review the current understanding of novel protein interaction networks and the contribution of the lipid membrane environment to UPR activation.

Keywords:  Chaperone; Unfolded Protein Response; disordered regions; lipid bilayer stress

DOI:  https://doi.org/10.1016/j.biocel.2024.106598
Int J Mol Sci. 2024 May 07. pii: 5101. [Epub ahead of print]25(10):

p20BAP31 Induces Autophagy in Colorectal Cancer Cells by Promoting PERK-Mediated ER Stress.

Xiaohan Jiang, Guoxun Li, Benzhi Zhu, Jiaying Yang, Shuyu Cui, Rui Jiang, Bing Wang.

  B-cell receptor-associated protein 31 (BAP31) is an endoplasmic reticulum (ER) membrane protein involved in apoptosis and autophagy by communication with ER and mitochondria. BAP31 is cleaved by caspase-8 and generates a proapoptotic fragment, p20BAP31, which has shown to induce ER stress and apoptosis through multiple pathways. In this study, we found that p20BAP31 significantly increased the agglomeration of LC3 puncta, suggesting the occurrence of autophagy. Therefore, it is meaningful to explore the mechanism of p20BAP31-induced autophagy, and further analyze the relationships among p20BAP31-induced autophagy, ER stress and apoptosis. The data showed that p20BAP31 induced autophagy by inhibition of the PI3K/AKT/mTOR signaling in colorectal cells. ER stress inhibitor 4-PBA and PERK siRNA alleviated p20BAP31-induced autophagy; in turn, autophagy inhibitors 3-MA and CQ did not affect p20BAP31-induced ER stress, suggesting that p20BAP31-induced ER stress is the upstream of autophagy. We also discovered that ROS inhibitor NAC inhibited p20BAP31-induced autophagy. Furthermore, inhibition of autophagy by CQ suppressed p20BAP31-induced apoptosis and ameliorated cell proliferation. Importantly, p20BAP31 markedly reduced the tumor size in vivo, and significantly enhanced the autophagy levels in the tumor tissues. Collectively, p20BAP31 initiates autophagy by inhibiting the PI3K/AKT/mTOR signaling and activating the PERK-mediated ROS accumulation, further promotes p20BAP31-induced apoptosis and ultimately results in cell death. This study comprehensively reveals the potential mechanism of p20BAP31-induced cell death, which may provide new strategies for antitumor therapy.

Keywords:  ER stress; PI3K/AKT/mTOR; apoptosis; autophagy; colorectal cancer; p20BAP31

DOI:  https://doi.org/10.3390/ijms25105101
Hematol Oncol. 2024 May;42(3): e3281

FLT3-ITD regulation of the endoplasmic reticulum functions in acute myeloid leukemia.

María Turos-Cabal, Ana M Sánchez-Sánchez, Noelia Puente-Moncada, Federico Herrera, Isaac Antolin, Carmen Rodríguez, Vanesa Martín.

  The FLT3-ITD mutation represents the most frequent genetic alteration in newly diagnosed acute myeloid leukemia (AML) patient and is associated with poor prognosis. Mutation result in the retention of a constitutively active form of this receptor in the endoplasmic reticulum (ER) and the subsequent modification of its downstream effectors. Here, we assessed the impact of such retention on ER homeostasis and found that mutant cells present lower levels of ER stress due to the overexpression of ERO1α, one of the main proteins of the protein folding machinery at the ER. Overexpression of ERO1α resulted essential for ITD mutant cells survival and chemoresistance and also played a crucial role in shaping the type of glucose metabolism in AML cells, being the mitochondrial pathway the predominant one in those with a higher ER stress (non-mutated cells) and the glycolytic pathway the predominant one in those with lower ER stress (mutated cells). Our data indicate that FLT3 mutational status dictates the route for glucose metabolism in an ERO1α depending on manner and this provides a survival advantage to tumors carrying these ITD mutations.

Keywords:  ERO1α; FLT3; acute myeloid leukemia; endoplasmic reticulum; glucose metabolism; mitochondria associated membranes

DOI:  https://doi.org/10.1002/hon.3281
Int Rev Cell Mol Biol. 2024 ;pii: S1937-6448(24)00014-5. [Epub ahead of print]386 81-131

An Overview of the Unfolded Protein Response (UPR) and Autophagy Pathways in Human Viral Oncogenesis.

Shovan Dutta, Anirban Ganguly, Sounak Ghosh Roy.

  Autophagy and Unfolded Protein Response (UPR) can be regarded as the safe keepers of cells exposed to intense stress. Autophagy maintains cellular homeostasis, ensuring the removal of foreign particles and misfolded macromolecules from the cytoplasm and facilitating the return of the building blocks into the system. On the other hand, UPR serves as a shock response to prolonged stress, especially Endoplasmic Reticulum Stress (ERS), which also includes the accumulation of misfolded proteins in the ER. Since one of the many effects of viral infection on the host cell machinery is the hijacking of the host translational system, which leaves in its wake a plethora of misfolded proteins in the ER, it is perhaps not surprising that UPR and autophagy are common occurrences in infected cells, tissues, and patient samples. In this book chapter, we try to emphasize how UPR, and autophagy are significant in infections caused by six major oncolytic viruses-Epstein-Barr (EBV), Human Papilloma Virus (HPV), Human Immunodeficiency Virus (HIV), Human Herpesvirus-8 (HHV-8), Human T-cell Lymphotropic Virus (HTLV-1), and Hepatitis B Virus (HBV). Here, we document how whole-virus infection or overexpression of individual viral proteins in vitro and in vivo models can regulate the different branches of UPR and the various stages of macro autophagy. As is true with other viral infections, the relationship is complicated because the same virus (or the viral protein) exerts different effects on UPR and Autophagy. The nature of this response is determined by the cell types, or in some cases, the presence of diverse extracellular stimuli. The vice versa is equally valid, i.e., UPR and autophagy exhibit both anti-tumor and pro-tumor properties based on the cell type and other factors like concentrations of different metabolites. Thus, we have tried to coherently summarize the existing knowledge, the crux of which can hopefully be harnessed to design vaccines and therapies targeted at viral carcinogenesis.

Keywords:  ATF6; Autophagy; CHOP; EBV; ERS; HHV-8; HIV; HPV; HTLV-1; IRE1-α; PERK; UPR

DOI:  https://doi.org/10.1016/bs.ircmb.2024.01.004
PLoS Pathog. 2024 May 24. 20(5): e1012266

Mycoplasma glycine cleavage system key subunit GcvH is an apoptosis inhibitor targeting host endoplasmic reticulum.

Qiao Pan, Yujuan Zhang, Tong Liu, Qingyuan Xu, Qi Wu, Jiuqing Xin.

Mycoplasmas are minimal but notorious bacteria that infect humans and animals. These genome-reduced organisms have evolved strategies to overcome host apoptotic defense and establish persistent infection. Here, using Mycoplasma bovis as a model, we demonstrate that mycoplasma glycine cleavage system (GCS) H protein (GcvH) targets the endoplasmic reticulum (ER) to hijack host apoptosis facilitating bacterial infection. Mechanically, GcvH interacts with the ER-resident kinase Brsk2 and stabilizes it by blocking its autophagic degradation. Brsk2 subsequently disturbs unfolded protein response (UPR) signaling, thereby inhibiting the key apoptotic molecule CHOP expression and ER-mediated intrinsic apoptotic pathway. CHOP mediates a cross-talk between ER- and mitochondria-mediated intrinsic apoptosis. The GcvH N-terminal amino acid 31-35 region is necessary for GcvH interaction with Brsk2, as well as for GcvH to exert anti-apoptotic and potentially pro-infective functions. Notably, targeting Brsk2 to dampen apoptosis may be a conserved strategy for GCS-containing mycoplasmas. Our study reveals a novel role for the conserved metabolic route protein GcvH in Mycoplasma species. It also sheds light on how genome-reduced bacteria exploit a limited number of genomic proteins to resist host cell apoptosis thereby facilitating pathogenesis.

DOI: https://doi.org/10.1371/journal.ppat.1012266
J Biol Chem. 2024 May 20. pii: S0021-9258(24)01899-4. [Epub ahead of print] 107398

LC3A-mediated autophagy elicits PERK-eIF2α-ATF4 axis activation and mitochondrial dysfunction: Exposing vulnerability in aggresome positive cancer cells.

Nada Amer, Dina Hesham, Nouran Al-Shehaby, Hisham A Elshoky, May Amer, Sameh Magdeldin, Manar Mansour, Khaled Abou-Aisha, Shahenda El-Naggar.

  The unfolded protein response pathways (UPR), autophagy, and compartmentalization of misfolded proteins into inclusion bodies are critical components of the protein quality control network. Among inclusion bodies, aggresomes are particularly intriguing due to their association with cellular survival, drug resistance, and cancer-aggressive behavior. Aggresomes are molecular condensates formed when collapsed vimentin cages encircle misfolded proteins before final removal by autophagy. Yet significant gaps persist in the mechanisms governing aggresome formation and elimination in cancer cells. Understanding these mechanisms is crucial, especially considering the involvement of LC3A, a member of the MAP1LC3 family, which plays a unique role in autophagy regulation and has been reported to be epigenetically silenced in many cancers. Herein, we utilized tetracycline-inducible expression of LC3A to investigate its role in choroid plexus carcinoma cells, which inherently exhibit the presence of aggresomes. Live cell imaging was employed to demonstrate the effect of LC3A expression on aggresome-positive cells, while SILAC-based proteomics identified LC3A-induced protein and pathway alterations. Our findings demonstrate that extended expression of LC3A is associated with cellular senescence. However, the obstruction of lysosomal degradation in this context has a deleterious effect on cellular viability. In response to LC3A-induced autophagy, we observed significant alterations in mitochondrial morphology, reflected by mitochondrial dysfunction and increased ROS production. Furthermore, LC3A expression elicited the activation of the PERK-eIF2α-ATF4 axis of the UPR, underscoring a significant change in protein quality control network. In conclusion, our results elucidate that LC3A-mediated autophagy alters the protein quality control network, exposing a vulnerability in aggresome-positive cancer cells.

Keywords:  Aggresomes; Autophagy; Endoplasmic reticulum; Inclusion bodies; MAP1LC3A; Protein quality control; Proteostasis; Senescence

DOI:  https://doi.org/10.1016/j.jbc.2024.107398
Cell Rep. 2024 May 17. pii: S2211-1247(24)00583-7. [Epub ahead of print]43(5): 114255

Upregulation of neuronal ER-phagy improves organismal fitness and alleviates APP toxicity.

Wenqing Mou, Yinglu Tang, Yunpeng Huang, Zhihao Wu, Yixian Cui.

  ER-phagy, a selective autophagy targeting the endoplasmic reticulum (ER) for lysosomal degradation through cargo receptors, plays a critical role in ER quality control and is linked to various diseases. However, its physiological and pathological roles remain largely unclear due to a lack of animal model studies. This study establishes Drosophila as an in vivo ER-phagy model. Starvation triggers ER-phagy across multiple fly tissues. Disturbing ER-phagy by either globally upregulating or downregulating ER-phagy receptors, Atl or Rtnl1, harms the fly. Notably, moderate upregulation of ER-phagy in fly brains by overexpressing Atl or Rtnl1 significantly attenuates age-associated neurodegenerations. Furthermore, in a Drosophila model of Alzheimer's disease expressing human amyloid precursor protein (APP), impaired ER-phagy is observed. Enhancing ER-phagy in the APP-expressing fly brain facilitates APP degradation, significantly alleviating disease symptoms. Therefore, our findings suggest that modulating ER-phagy may offer a therapeutic strategy to treat aging and diseases associated with ER protein aggregation.

Keywords:  APP; Atg8a; Atl; CP: Cell biology; CP: Molecular biology; ER-phagy; Rtnl1; aging; cargo receptor; macro-autophagy; neurodegeneration

DOI:  https://doi.org/10.1016/j.celrep.2024.114255
Brain Res. 2024 May 18. pii: S0006-8993(24)00265-8. [Epub ahead of print]1838 149011

Activation of the sigma-1 receptor ameliorates neuronal ferroptosis via IRE1α after spinal cord injury.

Rui Tan, Chunxiao Sui, Yuhang Diao, Guihong Shi, Xiaojun Hu, Zhenghao Hao, Chenyang Li, Mingyu Hao, Minghao Xie, Tao Zhu.

  Spinal Cord Injury (SCI) is a debilitating disease associated with a significant economic burden owing to its high level of disability; however, current treatment options have only limited efficacy. Past research has shown that iron-dependent programmed cell death, also known as ferroptosis, plays a critical role in the pathogenesis of SCI. The sigma-1 receptor (Sig-1R) is widely distributed in the central nervous system, and has been implicated in the pathophysiology of several neurological and psychiatric disorders. Several in vivo and ex vivo studies have shown that Sig-1R activation exerts unique neuroprotective effects. However, the underlying mechanisms remain unclear. To date, no study has yet demonstrated the association between Sig-1R activation and ferroptosis in patients with SCI. However, the present study found that Sig-1R activation effectively promoted the recovery of motor function in mice after spinal cord injury, attenuated neuronal apoptosis, reduced the production of pro-inflammatory cytokines and iron accumulation, and inhibited ferroptosis in spinal cord tissues following SCI in mice. Ferroptosis and IRE1α were significantly upregulated after spinal cord injury, while sigma-1 receptor agonists were able to facilitate this result through the elimination of inositol-requiring enzyme-1 alpha (IRE1α)-mediated neuronal ferroptosis. Therefore, sigma-1 receptor activation could attenuate ferroptosis after SCI by reducing IRE1α and improving functional recovery after SCI, potentially representing a new therapeutic strategy for treating SCI.

Keywords:  Ferroptosis; IRE1α; Sigma-1 receptor; Spinal cord injury

DOI:  https://doi.org/10.1016/j.brainres.2024.149011
Biochem Biophys Res Commun. 2024 Apr 25. pii: S0006-291X(24)00508-4. [Epub ahead of print]721 149972

Mitigation of ROS-triggered endoplasmic reticulum stress by upregulating Nrf2 retards diabetic nephropathy.

Xiaojiao Zeng, Yuanyuan Zhang, Ling Tian, Yin Zheng, Jingyun Zhang, Zhongming Wu.

  Endoplasmic reticulum stress (ERS) plays a crucial role in the pathogenesis of diabetic nephropathy (DN), and it is often accompanied by an increase in reactive oxygen species (ROS) production. However, the precise relationship between NFE2-related factor-2 (Nrf2), a key regulator of ROS balance, and ERS in DN remains elusive. This study aimed to investigate the impact of Nrf2 on ERS and its therapeutic potential in DN. Herein, ERS-related changes, including increased activating transcription factor-6 (ATF6), glucose-regulated protein 78 (GRP78), and transcription factor C/EBP homologous protein (CHOP) expression, were observed in the renal tissues of streptozotocin-induced DN mice and high glucose cultured human renal proximal tubular (HK-2) cells. Nrf2 knockdown increased the sensitivity of HK-2 cells to ERS under high glucose conditions, underscoring the regulatory role of Nrf2 in ERS modulation. Notably, upregulating Nrf2 in ezetimibe-treated diabetic mice restored ERS markers and ameliorated albuminuria, glomerular hypertrophy, mesangial expansion, and tubulointerstitial fibrosis. Furthermore, the inhibition of ERS in HK-2 cells by the ROS scavenger, N-acetylcysteine, highlights the interplay between ROS and ERS. This study, for the first time, elucidates that the upregulation of Nrf2 may alleviate the negative influence of ROS-mediated ERS, presenting a promising therapeutic avenue for delaying the progression of DN. These findings suggest a potential strategy for targeting Nrf2 and ERS in developing novel therapeutic interventions for DN.

Keywords:  Diabetic nephropathy; Endoplasmic reticulum stress; NFE2-Related factor 2; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.bbrc.2024.149972