bims-unfpre 2025-01-05 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2025–01–05
seven papers selected by
Susan Logue, University of Manitoba

Understanding the impact of ER stress on lung physiology.
Pleiotropic Function of Cellular Prion Protein: Encompassing Endoplasmic-Reticulum Stress, Cell Proliferation in Vascular Smooth Muscle Cells.
PDIA4 targets IRE1α/sXBP1 to alleviate NLRP3 inflammasome activation and renal tubular injury in diabetic kidney disease.
Microtubule acetylation and PERK activation facilitate eribulin-induced mitochondrial calcium accumulation and cell death.
Liver-specific gene PGRMC1 blocks c-Myc-induced hepatocarcinogenesis through ER stress-independent PERK activation.
Combination drug therapy prevents CIAKI by suppressing ER stress-induced apoptosis.
Stress-inducible phosphoprotein 1 (Sti1/Stip1/Hop) sequesters misfolded proteins during stress.

Front Cell Dev Biol. 2024 ;12 1466997

Understanding the impact of ER stress on lung physiology.

Zhiling Fu, Wei Wang, Yuan Gao.

  Human lungs consist of a distinctive array of cell types, which are subjected to persistent challenges from chemical, mechanical, biological, immunological, and xenobiotic stress throughout life. The disruption of endoplasmic reticulum (ER) homeostatic function, triggered by various factors, can induce ER stress. To overcome the elevated ER stress, an adaptive mechanism known as the unfolded protein response (UPR) is activated in cells. However, persistent ER stress and maladaptive UPR can lead to defects in proteostasis at the cellular level and are typical features of the lung aging. The aging lung and associated lung diseases exhibit signs of ER stress-related disruption in cellular homeostasis. Dysfunction resulting from ER stress and maladaptive UPR can compromise various cellular and molecular processes associated with aging. Hence, comprehending the mechanisms of ER stress and UPR components implicated in aging and associated lung diseases could enable to develop appropriate therapeutic strategies for the vulnerable population.

Keywords:  ERstress; aging; autophagy; lung dysfunction; upr

DOI:  https://doi.org/10.3389/fcell.2024.1466997
J Cell Biochem. 2025 Jan;126(1): e30692

Pleiotropic Function of Cellular Prion Protein: Encompassing Endoplasmic-Reticulum Stress, Cell Proliferation in Vascular Smooth Muscle Cells.

Rumela Bose, Madhubanti Ghosh, Rupasri Ain.

  Cellular prion protein (PRNP) has been implicated in various physiological processes in different cell types, for decades. Little has been known how PRNP functions in multiple, yet related processes within a particular system. In our current study, with the aid of high-throughput RNA-sequencing technique, we have presented an overall transcriptome profile of rat vascular smooth muscle cells (VSMCs) with Prnp knockdown. Fifty-one genes were found to be differentially regulated, of which, genes involved in cell proliferation and endoplasmic reticulum (ER) stress pathway, show significant upregulation. That PRNP negatively regulates VSMC proliferation, has been demonstrated using immunoblot assays, BrdU incorporation assay and Ki-67 immunofluorescence staining. As revealed from our RNA-Seq data, ATF4, a downstream effector of the PERK arm of ER stress pathway is upregulated upon RNA interference of Prnp in VSMCs. As a result, the expression of the functional phosphorylated isoform of translation initiation factor eIF2α (p-eIF2α) is elevated. Additionally, we also showed that downregulation of Prnp leads to excess intracellular ROS accumulation, subsequently leading to splicing of Xbp1 mRNA and triggering unfolded protein response (UPR) within the cell. Therefore, our findings highlight that PRNP directly or indirectly modulates an array of biological processes and plays a pivotal role in preserving the equilibrium between excess proliferation and optimal endoplasmic reticulum function, in VSMCs.

Keywords:  ATF4; RNA‐sequencing; ROS; eIF2α; transcriptome

DOI:  https://doi.org/10.1002/jcb.30692
Biochim Biophys Acta Mol Basis Dis. 2024 Dec 30. pii: S0925-4439(24)00639-2. [Epub ahead of print] 167645

PDIA4 targets IRE1α/sXBP1 to alleviate NLRP3 inflammasome activation and renal tubular injury in diabetic kidney disease.

Xuan Liu, Donghui Zhou, Yu Su, Hongling Liu, Qiuyue Su, Tianyu Shen, Mianzhi Zhang, Xue Mi, Yuying Zhang, Shijing Yue, Zhujun Zhang, Dekun Wang, Xiaoyue Tan.

  The role of ER stress in the pathogenesis of diabetic kidney diseases (DKD) remains unclear. We employed bioinformatics to identify the UPR pathway activation, inflammation, and programmed cell death patterns in diabetic tubules. Levels of IRE1α/sXBP1 signaling, NLRP3 inflammasome activity and pyroptosis in tubular cells under high glucose conditions were measured. IRE1α knockdown was used to determine its role in glucose-triggered activation of the NLRP3 inflammasome and pyroptosis. PDIA4 overexpression and silencing were used to assess its impact on the IRE1α/sXBP1 pathway. The dynamic interaction among PDIA4, GRP78, and IRE1α under high glucose were analyzed using immunoprecipitation and crosslinking assays. In STZ-induced and db/db mouse models of DKD, the regulatory role of PDIA4 on IRE1α/sXBP1 signaling and diabetic tubular inflammation and injury were evaluated. Our study showed that IRE1α/sXBP1, NLRP3 inflammasome, and pyroptosis are activated in the renal tubules of DKD patients. Induction of IRE1α pathway mediated the glucose-triggered activation of the NLRP3 inflammasome and pyroptosis. Moreover, overexpression of PDIA4 decreased the activation of IRE1α/sXBP1 under high glucose conditions. High glucose leads to the release of GRP78 from IRE1α and an increased interaction between IRE1α and PDIA4. In mouse models of DKD, overexpressing PDIA4 mitigated diabetic tubular injury and inflammation, marked by decreased IRE1α/sXBP1 and NLRP3 inflammasome. In conclusion, our findings demonstrate that high glucose triggers NLRP3 inflammasome and pyroptosis via the IRE1α/sXBP1 pathway in renal tubular cells. Overexpression of PDIA4 suppresses IRE1α signaling by binding to its oligomeric form, implying a promising therapeutic intervention for DKD.

Keywords:  Diabetic Kidney Disease; IRE1α; NLRP3 inflammasome; PDIA4; sXBP1

DOI:  https://doi.org/10.1016/j.bbadis.2024.167645
Cell Mol Life Sci. 2024 Dec 31. 82(1): 32

Microtubule acetylation and PERK activation facilitate eribulin-induced mitochondrial calcium accumulation and cell death.

Seongeun Song, Panseon Ko, Seula Keum, Jangho Jeong, Ye Eun Hwang, Minwoo Lee, Jee-Hye Choi, Youn-Sang Jung, Sung Hyun Kim, Sangmyung Rhee.

  Over the past few decades, microtubules have been targeted by various anticancer drugs, including paclitaxel and eribulin. Despite their promising effects, the development of drug resistance remains a challenge. We aimed to define a novel cell death mechanism that targets microtubules using eribulin and to assess its potential in overcoming eribulin resistance. Notably, treating non-resistant breast cancer cells with eribulin led to increased microtubule acetylation around the nucleus and cell death. Conversely, eribulin-resistant (EriR) cells did not exhibit a similar increase in acetylation, even at half-maximal inhibitory concentrations. Interestingly, silencing the ATAT1 gene, which encodes the α-tubulin N-acetyltransferase 1 (the enzyme responsible for microtubule acetylation), induces eribulin resistance, mirroring the phenotype of EriR cells. Moreover, eribulin-induced acetylation of microtubules facilitates the transport of Ca2+ from the ER to the mitochondria, releasing cytochrome c and subsequent cell death. Transcriptome analysis of EriR cells revealed a significant downregulation of ER stress-induced apoptotic signals, particularly the activity of protein kinase RNA-like ER kinase (PERK), within the unfolded protein response signaling system. Pharmacological induction of microtubule acetylation through a histone deacetylase 6 inhibitor combined with the activation of PERK signaling using the PERK activator CCT020312 in EriR cells enhanced mitochondrial Ca2+ accumulation and subsequent cell death. These findings reveal a novel mechanism by which eribulin-induced microtubule acetylation and increased PERK activity lead to Ca2+ overload from the ER to the mitochondria, ultimately triggering cell death. This study offers new insights into strategies for overcoming resistance to microtubule-targeting agents.

Keywords:  Calcium transfer; Drug resistance; ER-mitochondria contact; Eribulin; Microtubule acetylation; PERK signaling

DOI:  https://doi.org/10.1007/s00018-024-05565-w
Nat Commun. 2025 Jan 02. 16(1): 50

Liver-specific gene PGRMC1 blocks c-Myc-induced hepatocarcinogenesis through ER stress-independent PERK activation.

Fubo Ji, Jianjuan Zhang, Liping Mao, Yaqi Tan, Meihua Ye, Xianglei He, Yongzhi Zhao, Jiaxin Liu, Yan Zhang, Nachuan Zhang, Jiong Shi, Jianing Yan, Xiujun Cai, Bin Zhao, Jianping Jin, Pinglong Xu, Stephanie Roessler, Xin Zheng, Junfang Ji.

Roles of liver-specific genes (LSGs) in tumor initiation and progression are rarely explored in hepatocellular carcinoma (HCC). Here we show that LSGs are generally downregulated in HCC tumor tissues compared to non-HCC liver tissues, and low-LSG HCCs show poor prognosis and the activated c-Myc pathway. Among the c-Myc- and patient prognosis-associated LSGs, PGRMC1 significantly blocks c-Myc-induced orthotopic HCC formation. The role of PGRMC1 depends on its localization to the endoplasmic reticulum (ER) membrane, where PGRMC1 interacts with PERK through their ER luminal domains. This interaction in turn activates PERK in an ER stress-independent manner, which phosphorylates eIF2α and consequently inhibits c-Myc protein translation. In HCC patients, PGRMC1 level is significantly reduced in tumor tissues and negatively associated with the c-Myc signature. Patients with low-PGRMC1 in their tumors have poor prognosis. Collectively, deregulated LSGs in HCC are associated with the c-Myc pathway activation and PGRMC1 blocks c-Myc-induced hepatic carcinogenesis through promoting ER stress-independent PERK activation.

DOI: https://doi.org/10.1038/s41467-024-55745-2
Sci Rep. 2024 Dec 30. 14(1): 32074

Combination drug therapy prevents CIAKI by suppressing ER stress-induced apoptosis.

Xuan Wang, Shan Han, Lili Zhao, Hongliang Cong.

  Contrast-induced acute kidney injury (CIAKI) is an important clinical complication that occurs after the application of contrast agent in percutaneous coronary intervention. The pathogenesis of CIAKI is complex. Studies have shown that cell apoptosis induced by endoplasmic reticulum stress (ERS) plays an important role in renal tubular injury in CIAKI. These findings suggest that atorvastatin, probucol and alprostadil can inhibit renal tubular cell apoptosis to prevent CIAKI. However, there is no specific research on the above effects of drug combinations. Therefore, this study aimed to establish a rat CIAKI model with meglumine diatrizoate and add drug intervention to compare the influence of combined drugs with that of atorvastatin alone on CIAKI via the inhibition of ERS-specific molecular chaperones. Fifty Wistar rats were randomly divided into 5 groups: Group A + CC (atorvastatin group, n = 10); Group PA + CC (probucol + atorvastatin group, n = 10); Group AA + CC (alprostadil + atorvastatin group, n = 10); Group PCC (contrast group, n = 10); and Group NCC (control group, n = 10). Among the five groups, Group PCC presented the significantly highest creatinine increase rate and protein and nucleic acid expression levels, with the most severe cell injury and apoptosis observed via HE and TUNEL staining. Compared with those in the atorvastatin group, the rate of increase in creatinine and protein expression in the combined treatment groups were decreased to some extent, and the histological morphology was also improved. This was especially evident in Group AA + CC. Renal cell apoptosis induced by the ERS pathway may play an important role in the pathogenesis of CIAKI induced by meglumine diatrizoate. Atorvastatin, probucol and alprostadil can prevent the occurrence of CIAKI, and the ERS-induced apoptosis pathway is involved in this mechanism. The protective effect of probucol or alprostadil combined with atorvastatin on CIAKI may be stronger than that of atorvastatin alone, with a greater effect of the combination of alprostadil and atorvastatin.

Keywords:  Alprostadil; Apoptosis; Atorvastatin; Contrast-induced acute kidney injury; Endoplasmic reticulum stress; Probucol

DOI:  https://doi.org/10.1038/s41598-024-83741-5
FEBS J. 2024 Dec 30.

Stress-inducible phosphoprotein 1 (Sti1/Stip1/Hop) sequesters misfolded proteins during stress.

Benjamin S Rutledge, Young J Kim, Donovan W McDonald, Juan C Jurado-Coronel, Marco A M Prado, Jill L Johnson, Wing-Yiu Choy, Martin L Duennwald.

  Co-chaperones are key elements of cellular protein quality control. They cooperate with the major heat shock proteins Hsp70 and Hsp90 in folding proteins and preventing the toxic accumulation of misfolded proteins upon exposure to stress. Hsp90 interacts with the co-chaperone stress-inducible phosphoprotein 1 (Sti1/Stip1/Hop) and activator of Hsp90 ATPase protein 1 (Aha1) among many others. Sti1 and Aha1 control the ATPase activity of Hsp90, but Sti1 also facilitates the transfer of client proteins from Hsp70 to Hsp90, thus connecting these two major branches of protein quality control. We find that misbalanced expression of Sti1 and Aha1 in yeast and mammalian cells causes severe growth defects. Also, deletion of STI1 causes an accumulation of soluble misfolded ubiquitinated proteins and a strong activation of the heat shock response. We discover that, during proteostatic stress, Sti1 forms cytoplasmic inclusions in yeast and mammalian cells that overlap with misfolded proteins. Our work indicates a key role of Sti1 in proteostasis independent of its Hsp90 ATPase regulatory functions by sequestering misfolded proteins during stress.

Keywords:  Sti1; co‐chaperone; protein homeostasis; scaffolding; yeast

DOI:  https://doi.org/10.1111/febs.17389