bims-unfpre 2023-10-08 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2023‒10‒08
seven papers selected by
Susan Logue, University of Manitoba

Physiological ER stress caused by amylase production induces regulated Ire1-dependent mRNA decay in Aspergillus oryzae.
Loss of DDRGK1 impairs IRE1α UFMylation in spondyloepiphyseal dysplasia.
UFMylation of HRD1 regulates endoplasmic reticulum homeostasis.
Altered cartilage gene expression in Aga2 OI mouse negatively impacts linear growth through Sox9 and FGF signaling.
PACS-2 deficiency aggravates tubular injury in diabetic kidney disease by inhibiting ER-phagy.
Ablation of ERO1A induces lethal endoplasmic reticulum stress responses and immunogenic cell death to activate anti-tumor immunity.
Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress.

Commun Biol. 2023 Oct 04. 6(1): 1009

Physiological ER stress caused by amylase production induces regulated Ire1-dependent mRNA decay in Aspergillus oryzae.

Mizuki Tanaka, Silai Zhang, Shun Sato, Jun-Ichi Yokota, Yuko Sugiyama, Yasuaki Kawarasaki, Youhei Yamagata, Katsuya Gomi, Takahiro Shintani.

Regulated Ire1-dependent decay (RIDD) is a feedback mechanism in which the endoribonuclease Ire1 cleaves endoplasmic reticulum (ER)-localized mRNAs encoding secretory and membrane proteins in eukaryotic cells under ER stress. RIDD is artificially induced by chemicals that generate ER stress; however, its importance under physiological conditions remains unclear. Here, we demonstrate the occurrence of RIDD in filamentous fungus using Aspergillus oryzae as a model, which secretes copious amounts of amylases. α-Amylase mRNA was rapidly degraded by IreA, an Ire1 ortholog, depending on its ER-associated translation when mycelia were treated with dithiothreitol, an ER-stress inducer. The mRNA encoding maltose permease MalP, a prerequisite for the induction of amylolytic genes, was also identified as an RIDD target. Importantly, RIDD of malP mRNA is triggered by inducing amylase production without any artificial ER stress inducer. Our data provide the evidence that RIDD occurs in eukaryotic microorganisms under physiological ER stress.

DOI: https://doi.org/10.1038/s42003-023-05386-w
Int J Biol Sci. 2023 ;19(15): 4709-4725

Loss of DDRGK1 impairs IRE1α UFMylation in spondyloepiphyseal dysplasia.

Xiao Yang, Tangjun Zhou, Xin Wang, Ying Xia, Xiankun Cao, Xiaofei Cheng, Yu Cao, Peixiang Ma, Hui Ma, An Qin, Jie Zhao.

  Spondyloepiphyseal dysplasia (SEMD) is a rare disease in which cartilage growth is disrupted, and the DDRGK1 mutation is one of the causative genes. In our study, we established Ddrgk1fl/fl, Col2a1-ERT Cre mice, which showed a thickened hypertrophic zone (HZ) in the growth plate, simulating the previous reported SEMD pathology in vivo. Instead of the classical modulation mechanism towards SOX9, our further mechanism study found that DDRGK1 stabilizes the stress sensor endoplasmic reticulum-to-nucleus signaling 1 (IRE1α) to maintain endoplasmic reticulum (ER) homoeostasis. The loss of DDRGK1 decreased the UFMylation and subsequently led to increased ubiquitylation-mediated IRE1α degradation, causing ER dysfunction and activating the PERK/CHOP/Caspase3 apoptosis pathway. Further DDRGK1 K268R-mutant mice revealed the importance of K268 UFMylation site in IRE1α degradation and subsequent ER dysfunction. In conclusion, DDRGK1 stabilizes IRE1α to ameliorate ER stress and following apoptosis in chondrocytes, which finally promote the normal chondrogenesis.

Keywords:  DDRGK1; IRE1α; apoptosis; endoplasmic reticulum stress; spondyloepiphyseal dysplasia

DOI:  https://doi.org/10.7150/ijbs.82765
FASEB J. 2023 Nov;37(11): e23221

UFMylation of HRD1 regulates endoplasmic reticulum homeostasis.

Hui Luo, Qi-Bin Jiao, Chuan-Bin Shen, Wen-Yan Gong, Jing-Hua Yuan, Ying-Ying Liu, Zhen Chen, Jiang Liu, Xiao-Ling Xu, Yu-Sheng Cong, Xing-Wei Zhang.

  Ubiquitin fold modifier 1 is a small ubiquitin-like protein modifier that is essential for embryonic development of metazoans. Although UFMylation has been connected to endoplasmic reticulum homeostasis, the underlying mechanisms and the relevant cellular targets are largely unknown. Here, we show that HRD1, a ubiquitin ligase of ER-associated protein degradation (ERAD), is a novel substrate of UFM1 conjugation. HRD1 interacts with UFMylation components UFL1 and DDRGK1 and is UFMylated at Lys610 residue. In UFL1-depleted cells, the stability of HRD1 is increased and its ubiquitination modification is reduced. In the event of ER stress, the UFMylation and ubiquitination modification of HRD1 is gradually inhibited over time. Alteration of HRD1 Lys610 residue to arginine impairs its ability to degrade unfolded or misfolded proteins to disturb protein processing in ER. These results suggest that UFMylation of HRD1 facilitates ERAD function to maintain ER homeostasis.

Keywords:  ER homeostasis; ER-associated protein degradation; HRD1; UFL1; UFMylation

DOI:  https://doi.org/10.1096/fj.202300004RRRR
JCI Insight. 2023 Oct 05. pii: e171984. [Epub ahead of print]

Altered cartilage gene expression in Aga2 OI mouse negatively impacts linear growth through Sox9 and FGF signaling.

Jennifer Zieba, Lisette Nevarez, Davis Wachtell, Jorge H Martin, Alexander Kot, Sereen Wong, Daniel H Cohn, Deborah Krakow.

  Osteogenesis imperfecta (OI), brittle bone disease, is a disorder characterized by bone fragility and increased fracture incidence. All forms of OI also feature short stature, implying an effect on endochondral ossification. Using the Aga2+/- mouse, which has a mutation in type I collagen, we show an affected growth plate primarily due to a shortened proliferative zone. We used scRNAseq analysis of tibial and femoral growth plate tissues to understand transcriptional consequences on growth plate cell types. We show that perichondrial cells, which express abundant type I procollagen, and growth plate chondrocytes, which were found to express low amounts of type I procollagen, had ER stress and dysregulation of the same UPR pathway as previously demonstrated in osteoblasts. Aga2+/- proliferating chondrocytes showed increased FGF and MAPK signaling, findings consistent with accelerated differentiation. There was also increased Sox9 expression throughout the growth plate, which is expected to accelerate early chondrocyte differentiation but reduce late hypertrophic differentiation. These data reveal that mutant type I collagen expression in OI has a previously unappreciated impact on the cartilage growth plate. These effects on endochondral ossification indicate that OI is a biologically complex phenotype going beyond its known impacts on bone to negatively affect linear growth.

Keywords:  Bone Biology; Cartilage; Cell stress; Development; Genetic diseases

DOI:  https://doi.org/10.1172/jci.insight.171984
Cell Death Dis. 2023 Oct 04. 14(10): 649

PACS-2 deficiency aggravates tubular injury in diabetic kidney disease by inhibiting ER-phagy.

Jinfei Yang, Li Li, Chenrui Li, Wei Chen, Yan Liu, Shilu Luo, Chanyue Zhao, Yachun Han, Ming Yang, Hao Zhao, Na Jiang, Yiyun Xi, Chengyuan Tang, Juan Cai, Li Xiao, Huafeng Liu, Lin Sun.

Autophagy of endoplasmic reticulum (ER-phagy) selectively removes damaged ER through autophagy-lysosome pathway, acting as an adaptive mechanism to alleviate ER stress and restore ER homeostasis. However, the role and precise mechanism of ER-phagy in tubular injury of diabetic kidney disease (DKD) remain obscure. In the present study, we demonstrated that ER-phagy of renal tubular cells was severely impaired in streptozocin (STZ)-induced diabetic mice, with a decreased expression of phosphofurin acidic cluster sorting protein 2 (PACS-2), a membrane trafficking protein which was involved in autophagy, and a reduction of family with sequence similarity 134 member B (FAM134B), one ER-phagy receptor. These changes were further aggravated in mice with proximal tubule specific knockout of Pacs-2 gene. In vitro, transfection of HK-2 cells with PACS-2 overexpression plasmid partially improved the impairment of ER-phagy and the reduction of FAM134B, both of which were induced in high glucose ambience; while the effect was blocked by FAM134B siRNA. Mechanistically, PACS-2 interacted with and promoted the nuclear translocation of transcription factor EB (TFEB), which was reported to activate the expression of FAM134B. Collectively, these data unveiled that PACS-2 deficiency aggravates renal tubular injury in DKD via inhibiting ER-phagy through TFEB/FAM134B pathway.

DOI: https://doi.org/10.1038/s41419-023-06175-3
Cell Rep Med. 2023 Sep 25. pii: S2666-3791(23)00373-7. [Epub ahead of print] 101206

Ablation of ERO1A induces lethal endoplasmic reticulum stress responses and immunogenic cell death to activate anti-tumor immunity.

Lihui Liu, Sini Li, Yan Qu, Hua Bai, Xiangyu Pan, Jian Wang, Zhijie Wang, Jianchun Duan, Jia Zhong, Rui Wan, Kailun Fei, Jiachen Xu, Li Yuan, Chao Wang, Pei Xue, Xue Zhang, Zixiao Ma, Jie Wang.

  Immunophenotyping of the tumor microenvironment (TME) is essential for enhancing immunotherapy efficacy. However, strategies for characterizing the TME exhibit significant heterogeneity. Here, we show that endoplasmic reticular oxidoreductase-1α (ERO1A) mediates an immune-suppressive TME and attenuates the response to PD-1 blockade. Ablation of ERO1A in tumor cells substantially incites anti-tumor T cell immunity and promotes the efficacy of aPD-1 in therapeutic models. Single-cell RNA-sequencing analyses confirm that ERO1A correlates with immunosuppression and dysfunction of CD8+ T cells along anti-PD-1 treatment. In human lung cancer, high ERO1A expression is associated with a higher risk of recurrence following neoadjuvant immunotherapy. Mechanistically, ERO1A ablation impairs the balance between IRE1α and PERK signaling activities and induces lethal unfolded protein responses in tumor cells undergoing endoplasmic reticulum stress, thereby enhancing anti-tumor immunity via immunogenic cell death. These findings reveal how tumor ERO1A induces immunosuppression, highlighting its potential as a therapeutic target for cancer immunotherapy.

Keywords:  ERO1A; endoplasmic reticulum stress response; immune target; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xcrm.2023.101206
Nat Commun. 2023 Oct 04. 14(1): 6201

Cytoplasmic Endonuclease G promotes nonalcoholic fatty liver disease via mTORC2-AKT-ACLY and endoplasmic reticulum stress.

Wenjun Wang, Junyang Tan, Xiaomin Liu, Wenqi Guo, Mengmeng Li, Xinjie Liu, Yanyan Liu, Wenyu Dai, Liubing Hu, Yimin Wang, Qiuxia Lu, Wen Xing Lee, Hong-Wen Tang, Qinghua Zhou.

Endonuclease G (ENDOG), a nuclear-encoded mitochondrial intermembrane space protein, is well known to be translocated into the nucleus during apoptosis. Recent studies have shown that ENDOG might enter the mitochondrial matrix to regulate mitochondrial genome cleavage and replication. However, little is known about the role of ENDOG in the cytosol. Our previous work showed that cytoplasmic ENDOG competitively binds with 14-3-3γ, which released TSC2 to repress mTORC1 signaling and induce autophagy. Here, we demonstrate that cytoplasmic ENDOG could also release Rictor from 14-3-3γ to activate the mTORC2-AKT-ACLY axis, resulting in acetyl-CoA production. Importantly, we observe that ENDOG could translocate to the ER, bind with Bip, and release IRE1a/PERK to activate the endoplasmic reticulum stress response, promoting lipid synthesis. Taken together, we demonstrate that loss of ENDOG suppresses acetyl-CoA production and lipid synthesis, along with reducing endoplasmic reticulum stress, which eventually alleviates high-fat diet-induced nonalcoholic fatty liver disease in female mice.

DOI: https://doi.org/10.1038/s41467-023-41757-x