bims-lypmec 2023-08-06 papers

Nat Commun. 2023 07 31. 14(1): 4494

Lysophosphatidylserine induces necrosis in pressure overloaded male mouse hearts via G protein coupled receptor 34.

Heart failure is a leading cause of mortality in developed countries. Cell death is a key player in the development of heart failure. Calcium-independent phospholipase A2β (iPLA2β) produces lipid mediators by catalyzing lipids and induces nuclear shrinkage in caspase-independent cell death. Here, we show that lysophosphatidylserine generated by iPLA2β induces necrotic cardiomyocyte death, as well as contractile dysfunction mediated through its receptor, G protein-coupled receptor 34 (GPR34). Cardiomyocyte-specific iPLA2β-deficient male mice were subjected to pressure overload. While control mice showed left ventricular systolic dysfunction with necrotic cardiomyocyte death, iPLA2β-deficient mice preserved cardiac function. Lipidomic analysis revealed a reduction of 18:0 lysophosphatidylserine in iPLA2β-deficient hearts. Knockdown of Gpr34 attenuated 18:0 lysophosphatidylserine-induced necrosis in neonatal male rat cardiomyocytes, while the ablation of Gpr34 in male mice reduced the development of pressure overload-induced cardiac remodeling. Thus, the iPLA2β-lysophosphatidylserine-GPR34-necrosis signaling axis plays a detrimental role in the heart in response to pressure overload.

DOI: https://doi.org/10.1038/s41467-023-40201-4

EMBO J. 2023 Jul 31. e111252

RNF26 binds perinuclear vimentin filaments to integrate ER and endolysosomal responses to proteotoxic stress.

Tom Cremer, Lenard M Voortman, Erik Bos, Marlieke Lm Jongsma, Laurens R Ter Haar, Jimmy Jll Akkermans, Cami Mp Talavera Ormeño, Ruud Hm Wijdeven, Jelle de Vries, Robbert Q Kim, George Mc Janssen, Peter A van Veelen, Roman I Koning, Jacques Neefjes, Ilana Berlin.

Proteotoxic stress causes profound endoplasmic reticulum (ER) membrane remodeling into a perinuclear quality control compartment (ERQC) for the degradation of misfolded proteins. Subsequent return to homeostasis involves clearance of the ERQC by endolysosomes. However, the factors that control perinuclear ER integrity and dynamics remain unclear. Here, we identify vimentin intermediate filaments as perinuclear anchors for the ER and endolysosomes. We show that perinuclear vimentin filaments engage the ER-embedded RING finger protein 26 (RNF26) at the C-terminus of its RING domain. This restricts RNF26 to perinuclear ER subdomains and enables the corresponding spatial retention of endolysosomes through RNF26-mediated membrane contact sites (MCS). We find that both RNF26 and vimentin are required for the perinuclear coalescence of the ERQC and its juxtaposition with proteolytic compartments, which facilitates efficient recovery from ER stress via the Sec62-mediated ER-phagy pathway. Collectively, our findings reveal a scaffolding mechanism that underpins the spatiotemporal integration of organelles during cellular proteostasis.

Keywords: ER stress; ERphagy; RNF26; endolysosomes; intermediate filaments

DOI: https://doi.org/10.15252/embj.2022111252

Curr Opin Cell Biol. 2023 Jul 27. pii: S0955-0674(23)00061-3. [Epub ahead of print]83 102212

Piecing together the structural organisation of lipid exchange at membrane contact sites.

Rasha Khaddaj, Wanda Kukulski.

Membrane contact sites (MCSs) are areas of close proximity between organelles, implicated in transport of small molecules and in organelle biogenesis. Lipid transfer proteins at MCSs facilitate the distribution of lipid species between organelle membranes. Such exchange processes rely on the apposition of two different membranes delimiting distinct compartments and a cytosolic intermembrane space. Maintaining organelle identity while transferring molecules therefore implies control over MCS architecture both on the ultrastructural and molecular levels. Factors including intermembrane distance, density of resident proteins, and contact surface area fine-tune MCS function. Furthermore, the structural arrangement of lipid transfer proteins and associated proteins underpins the molecular mechanisms of lipid fluxes at MCSs. Thus, the architecture of MCSs emerges as an essential aspect of their function.

DOI: https://doi.org/10.1016/j.ceb.2023.102212

Metabolism. 2023 Jul 28. pii: S0026-0495(23)00266-4. [Epub ahead of print] 155662

Transcription factor EB: A potential integrated network regulator in metabolic-associated cardiac injury.

Weixing Wen, Haoxiao Zheng, Weiwen Li, Guolin Huang, Peng Chen, Xiaolin Zhu, Yue Cao, Jiahuan Li, Xiaohui Huang, Yuli Huang.

With the worldwide pandemic of metabolic diseases, such as obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD), cardiometabolic disease (CMD) has become a significant cause of death in humans. However, the pathophysiology of metabolic-associated cardiac injury is complex and not completely clear, and it is important to explore new strategies and targets for the treatment of CMD. A series of pathophysiological disturbances caused by metabolic disorders, such as insulin resistance (IR), hyperglycemia, hyperlipidemia, mitochondrial dysfunction, oxidative stress, inflammation, endoplasmic reticulum stress (ERS), autophagy dysfunction, calcium homeostasis imbalance, and endothelial dysfunction, may be related to the incidence and development of CMD. Transcription Factor EB (TFEB), as a transcription factor, has been extensively studied for its role in regulating lysosomal biogenesis and autophagy. Recently, the regulatory role of TFEB in other biological processes, including the regulation of glucose homeostasis, lipid metabolism, etc. has been gradually revealed. In this review, we will focus on the relationship between TFEB and IR, lipid metabolism, endothelial dysfunction, oxidative stress, inflammation, ERS, calcium homeostasis, autophagy, and mitochondrial quality control (MQC) and the potential regulatory mechanisms among them, to provide a comprehensive summary for TFEB as a potential new therapeutic target for CMD. The integrated regulatory role of TFEB in metabolic-associated cardiac injury. When the body encounters metabolic disorders, it causes a series of pathophysiological reactions including insulin resistance, hyperglycemia, hyperlipidemia, endothelial dysfunction, oxidative stress, inflammation, endoplasmic reticulum stress, impaired calcium handling, autophagy dysregulation, mitochondrial dysfunction, ultimately leading to metabolic-associated cardiac injury. TFEB not only plays an important regulatory role in autophagy but also shows great potential in regulating insulin resistance, oxidative stress, inflammation, endoplasmic reticulum stress, calcium homeostasis, lipid metabolism, endothelial function, and mitochondrial quality control.

Keywords: Autophagy; Calcium homeostasis; Cardiometabolic disease; Endoplasmic reticulum stress; Endothelial dysfunction; Inflammation; Insulin resistance; Lipid metabolism; Metabolic-associated cardiac injury; Mitochondrial quality control; Oxidative stress; Transcription factor EB

DOI: https://doi.org/10.1016/j.metabol.2023.155662

Sci Adv. 2023 Aug 02. 9(31): eadd4222

NPRC deletion attenuates cardiac fibrosis in diabetic mice by activating PKA/PKG and inhibiting TGF-β1/Smad pathways.

Linlin Meng, Yue Lu, Xinlu Wang, Cheng Cheng, Fei Xue, Lin Xie, Yaoyuan Zhang, Wenhai Sui, Meng Zhang, Yun Zhang, Cheng Zhang.

Cardiac fibrosis plays a key role in the progression of diabetic cardiomyopathy (DCM). Previous studies demonstrated the cardioprotective effects of natriuretic peptides. However, the effects of natriuretic peptide receptor C (NPRC) on cardiac fibrosis in DCM remains unknown. Here, we observed that myocardial NPRC expression was increased in mice and patients with DCM. NPRC-/- diabetic mice showed alleviated cardiac fibrosis, as well as improved cardiac function and remodeling. NPRC knockdown in both cardiac fibroblasts and cardiomyocytes decreased collagen synthesis and proliferation of cardiac fibroblasts. RNA sequencing identified that NPRC deletion up-regulated the expression of TGF-β-induced factor homeobox 1 (TGIF1), which inhibited the phosphorylation of Smad2/3. Furthermore, TGIF1 up-regulation was mediated by the activation of cAMP/PKA and cGMP/PKG signaling induced by NPRC deletion. These findings suggest that NPRC deletion attenuated cardiac fibrosis and improved cardiac remodeling and function in diabetic mice, providing a promising approach to the treatment of diabetic cardiac fibrosis.

DOI: https://doi.org/10.1126/sciadv.add4222

Mol Cell. 2023 Jul 28. pii: S1097-2765(23)00526-9. [Epub ahead of print]

O-GlcNAcylation of Raptor transduces glucose signals to mTORC1.

Chenchen Xu, Xiaoqing Pan, Dong Wang, Yuanyuan Guan, Wenyu Yang, Xing Chen, Ying Liu.

The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient levels. Dysregulation of mTORC1 results in a broad spectrum of diseases. Glucose is the primary energy supply of cells, and therefore, glucose levels must be accurately conveyed to mTORC1 through highly responsive signaling mechanisms to control mTORC1 activity. Here, we report that glucose-induced mTORC1 activation is regulated by O-GlcNAcylation of Raptor, a core component of mTORC1, in HEK293T cells. Mechanistically, O-GlcNAcylation of Raptor at threonine 700 facilitates the interactions between Raptor and Rag GTPases and promotes the translocation of mTOR to the lysosomal surface, consequently activating mTORC1. In addition, we show that AMPK-mediated phosphorylation of Raptor suppresses Raptor O-GlcNAcylation and inhibits Raptor-Rags interactions. Our findings reveal an exquisitely controlled mechanism, which suggests how glucose coordinately regulates cellular anabolism and catabolism.

Keywords: O-GlcNAcylation; Raptor; glucose sensing; mTOR

DOI: https://doi.org/10.1016/j.molcel.2023.07.011