bims-ershed 2022-10-09 papers

Biochim Biophys Acta Rev Cancer. 2022 Oct 01. pii: S0304-419X(22)00139-1. [Epub ahead of print] 188814

Unfolded protein response at the cross roads of tumourigenesis, oxygen sensing and drug resistance in clear cell renal cell carcinoma.

Yew Hwang Chee, Afshin Samali, Claire M Robinson.

Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer. Despite therapeutic advances, long term survival in patients diagnosed with advanced disease is low. Efforts to understand the mechanisms promoting disease progression will likely produce novel therapeutic targets. The unfolded protein response (UPR) is activated when unfolded protein accumulates in the endoplasmic reticulum (ER) upon cellular stress. Constitutive UPR activation is a characteristic of many malignancies. We discuss the accumulating evidence that describes a role for the UPR in ccRCC. Studies focused on UPR signalling may provide compelling avenues for therapeutic intervention in the future.

Keywords: Clear cell renal cell carcinoma (ccRCC); Tumourigenesis; Unfolded protein response (UPR)

DOI: https://doi.org/10.1016/j.bbcan.2022.188814

J Heart Lung Transplant. 2022 Aug 20. pii: S1053-2498(22)02076-9. [Epub ahead of print]

Prevention of alloimmune rejection using XBP1-deleted bone marrow-derived dendritic cells in heart transplantation.

Kailun Sun, Chanyuan Fan, Ji Zhang, Haiqiang Ni, Mengqin Wang, Jiasi Zhang, Qingwen Li, Baicheng Kuang, Zhiheng Wang, Shuaiheng Hou, Nianqiao Gong.

BACKGROUND: Genetically modified dendritic cells (DCs) modulate the alloimmunity of T lymphocytes by regulating antigen presentation.
METHODS: We generated mice with specific deletion of the X-box-binding protein 1 (XBP1) allele in bone marrow cells and cultured bone marrow-derived DCs (Xbp1-/- BMDCs) from these animals. We then tested the phenotype of Xbp1-/- BMDCs, evaluated their capability to activate allogeneic T cells and investigated their mechanistic actions. We developed a mouse model of allogeneic heart transplantation in which recipients received PBS, Xbp1-/- BMDCs, a suboptimal dose of cyclosporine A (CsA), or Xbp1-/- BMDCs combined with a suboptimal dose of CsA to evaluate the effects of Xbp1-/- BMDC transfusion on alloimmunity and on the survival of heart allografts.
RESULTS: The deletion of XBP1 in BMDCs exploited the IRE1-dependent decay of TAPBP mRNA to reduce the expression of MHC-I on the cell surface, altered the capability of BMDCs to activate CD8+ T cells, and ultimately suppressed CD8+ T-cell-mediated allogeneic rejection. The adoptive transfer of Xbp1-/- BMDCs inhibited CD8+ T-cell-mediated rejection. In addition, XBP1-deficient BMDCs were weak stimulators of allogeneic CD4+ T cells despite expressing high levels of MHC-II and costimulatory molecules on their cell surface. Moreover, the adoptive transfer of Xbp1-/- BMDCs inhibited the production of circulating donor-specific IgG. The combination of Xbp1-/- BMDCs and CsA treatment significantly prolonged the survival of allografts compared to CsA alone.
CONCLUSIONS: The deletion of XBP1 induces immunosuppressive BMDCs, and treatment with these immunosuppressive BMDCs prevents alloimmune rejection and improves the outcomes of heart transplantation. This finding provides a promising therapeutic target in combating transplant rejection and expands knowledge of inducing therapeutic DCs.

Keywords: IRE1-dependent decay (RIDD); MHC-I; X-box-binding protein 1 (XBP1); dendritic cells (DCs); heart transplantation

DOI: https://doi.org/10.1016/j.healun.2022.08.010

Chemphyschem. 2022 Oct 08.

Elucidating the Implications of Diverse Dynamical Responses in p53 Protein.

Kajal Charan, Amitava Giri, Sandip Kar.

p53 is a well-known tumor suppressor gene that acts as a transcription factor to exhibit a variety of dynamical responses by sensing different types and extent of stress conditions causing DNA damage in Mammalian cells. Mathematical modeling has played a crucial role to correlate cell fate decision-making with some of these dynamic p53 regulations. However, it is extremely challenging to explain the various cell-type and stimulus-specific p53 protein dynamics under different stress conditions by using a single mathematical model. In this article, we propose a simple mathematical model of p53 regulation based on a generic p53 regulatory network that elucidates a range of p53 dynamical responses. By employing bifurcation analysis along with deterministic and stochastic simulations, we explain an array of p53 dynamics by correlating it with the corresponding cell fate regulations in a cell type-specific and stimulus-dependent manner. Moreover, our model makes experimentally testable predictions to fine-tune p53 dynamics under various DNA damage conditions and can be systematically used and improved to analyze complex p53 dynamics in the future.

Keywords: Computational chemistry, Kinetics, Protein-protein interaction, Biophysics, p53 dynamics

DOI: https://doi.org/10.1002/cphc.202200537

Cell Death Discov. 2022 Oct 04. 8(1): 407

Proteotoxic stress-induced apoptosis in cancer cells: understanding the susceptibility and enhancing the potency.

Luca Iuliano, Emiliano Dalla, Raffaella Picco, Showmeya Mallavarapu, Martina Minisini, Eleonora Malavasi, Claudio Brancolini.

Leiomyosarcoma (LMS) is aggressive cancer with few therapeutic options. LMS cells are more sensitive to proteotoxic stress compared to normal smooth muscle cells. We used small compound 2c to induce proteotoxic stress and compare the transcriptomic adaptations of immortalized human uterine smooth muscle cells (HUtSMC) and LMS cells SK-UT-1. We found that the expression of the heat shock proteins (HSPs) gene family is upregulated with higher efficiency in normal cells. In contrast, the upregulation of BH3-only proteins is higher in LMS cells. HSF1, the master regulator of HSP transcription, is sequestered into transcriptionally incompetent nuclear foci only in LMS cells, which explains the lower HSP upregulation. We also found that several compounds can enhance the cell death response to proteotoxic stress. Specifically, when low doses were used, an inhibitor of salt-inducible kinases (SIKs) and the inhibitor of IRE1α, a key element of the unfolded protein response (UPR), support proteotoxic-induced cell death with strength in LMS cells and without effects on the survival of normal cells. Overall, our data provide an explanation for the higher susceptibility of LMS cells to proteotoxic stress and suggest a potential option for co-treatment strategies.

DOI: https://doi.org/10.1038/s41420-022-01202-2

JHEP Rep. 2022 Nov;4(11): 100555

XBP1-mediated activation of the STING signalling pathway in macrophages contributes to liver fibrosis progression.

Qi Wang, Qingfa Bu, Mu Liu, Rui Zhang, Jian Gu, Lei Li, Jinren Zhou, Yuan Liang, Wantong Su, Zheng Liu, Mingming Wang, Zhexiong Lian, Ling Lu, Haoming Zhou.

Background & Aims: XBP1 modulates the macrophage proinflammatory response, but its function in macrophage stimulator of interferon genes (STING) activation and liver fibrosis is unknown. X-box binding protein 1 (XBP1) has been shown to promote macrophage nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3 (NLRP3) activation in steatohepatitis. Herein, we aimed to explore the underlying mechanism of XBP1 in the regulation of STING signalling and the subsequent NLRP3 activation during liver fibrosis.
Methods: XBP1 expression was measured in the human fibrotic liver tissue samples. Liver fibrosis was induced in myeloid-specific Xbp1-, STING-, and Nlrp3-deficient mice by carbon tetrachloride injection, bile duct ligation, or a methionine/choline-deficient diet.
Results: Although increased XBP1 expression was observed in the fibrotic liver macrophages of mice and clinical patients, myeloid-specific Xbp1 deficiency or pharmacological inhibition of XBP1 protected the liver against fibrosis. Furthermore, it inhibited macrophage NLPR3 activation in a STING/IRF3-dependent manner. Oxidative mitochondrial injury facilitated cytosolic leakage of macrophage self-mtDNA and cGAS/STING/NLRP3 signalling activation to promote liver fibrosis. Mechanistically, RNA sequencing analysis indicated a decreased mtDNA expression and an increased BCL2/adenovirus E1B interacting protein 3 (BNIP3)-mediated mitophagy activation in Xbp1-deficient macrophages. Chromatin immunoprecipitation (ChIP) assays further suggested that spliced XBP1 bound directly to the Bnip3 promoter and inhibited the transcription of Bnip3 in macrophages. Xbp1 deficiency decreased the mtDNA cytosolic release and STING/NLRP3 activation by promoting BNIP3-mediated mitophagy activation in macrophages, which was abrogated by Bnip3 knockdown. Moreover, macrophage XBP1/STING signalling contributed to the activation of hepatic stellate cells.
Conclusions: Our findings demonstrate that XBP1 controls macrophage cGAS/STING/NLRP3 activation by regulating macrophage self-mtDNA cytosolic leakage via BNIP3-mediated mitophagy modulation, thus providing a novel target against liver fibrosis.
Lay summary: Liver fibrosis is a typical progressive process of chronic liver disease, driven by inflammatory and immune responses, and is characterised by an excess of extracellular matrix in the liver. Currently, there is no effective therapeutic strategy for the treatment of liver fibrosis, resulting in high mortality worldwide. In this study, we found that myeloid-specific Xbp1 deficiency protected the liver against fibrosis in mice, while XBP1 inhibition ameliorated liver fibrosis in mice. This study concluded that targeting XBP1 signalling in macrophages may provide a novel strategy for protecting the liver against fibrosis.

Keywords: Acta2/α-SMA, actin, alpha 2, smooth muscle, aorta; BDL, bile duct ligation; BMDMs, bone marrow-derived macrophages; BNIP3; BNIP3, BCL2/adenovirus E1B interacting protein 3; CCl4, carbon tetrachloride; CM, conditional media; ChIP, chromatin immunoprecipitation; Col1a1, collagen, type I, alpha 1; DMXAA, 5,6-dimethylxanthenone-4-acetic acid; ER, endoplasmic reticulum; EtBr, ethidium bromide; HSC, hepatic stellate cell; IRE1α, inositol-requiring enzyme-1α; IRF3, interferon regulatory factor 3; KEGG, Kyoto Encyclopedia of Genes and Genomes; LC3B, microtubule-associated protein 1 light chain 3 beta; LPS, lipopolysaccharide; Liver fibrosis; MCD, methionine/choline-deficient diet; Macrophage; Mitophagy; MnSOD, manganese superoxide dismutase; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NLRP3, nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing 3; PBMCs, peripheral blood mononuclear cells; ROS, reactive oxygen species; STING; STING, stimulator of interferon genes; TBK1, TANK binding kinase 1; TGF-β1, transforming growth factor beta 1; TLR, Toll-like receptor; TNF-α, tumour necrosis factor alpha; Timp1, tissue inhibitor of matrix metalloproteinase 1; WT, wild-type; XBP1; XBP1, X-box binding protein 1; cGAS, cyclic GMP-AMP synthase; mtDNA; mtDNA, mitochondrial DNA; p62, sequestosome 1; sXBP1, spliced XBP1; shRNAs, short hairpin RNAs; uXBP1, unspliced XBP1

DOI: https://doi.org/10.1016/j.jhepr.2022.100555