bims-ershed 2022-03-20 papers

Biochim Biophys Acta Mol Basis Dis. 2022 Mar 15. pii: S0925-4439(22)00054-0. [Epub ahead of print] 166391

The unfolded protein response transducer IRE1α promotes reticulophagy in podocytes.

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

Glomerular diseases involving podocyte/glomerular epithelial cell (GEC) injury feature protein misfolding and endoplasmic reticulum (ER) stress. Inositol-requiring enzyme 1α (IRE1α) mediates chaperone production and autophagy during ER stress. We examined the role of IRE1α in selective autophagy of the ER (reticulophagy). Control and IRE1α knockout (KO) GECs were incubated with tunicamycin to induce ER stress and subjected to proteomic analysis. This showed IRE1α-dependent upregulation of secretory pathway mediators, including the coat protein complex II component Sec23B. Tunicamycin enhanced expression of Sec23B and the reticulophagy adaptor reticulon-3-long (RTN3L) in control, but not IRE1α KO GECs. Knockdown of Sec23B reduced autophagosome formation in response to ER stress. Tunicamycin stimulated colocalization of autophagosomes with Sec23B and RTN3L in an IRE1α-dependent manner. Similarly, during ER stress, glomerular α5 collagen IV colocalized with RTN3L and autophagosomes. Degradation of RTN3L and collagen IV increased in response to tunicamycin, and the turnover was blocked by deletion of IRE1α; thus, the IRE1α pathway promotes RTN3L-mediated reticulophagy and collagen IV may be an IRE1α-dependent reticulophagy substrate. In experimental glomerulonephritis, expression of Sec23B, RTN3L, and LC3-II increased in glomeruli of control mice, but not in podocyte-specific IRE1α KO littermates. In conclusion, during ER stress, IRE1α redirects a subset of Sec23B-positive vesicles to deliver RTN3L-coated ER fragments to autophagosomes. Reticulophagy is a novel outcome of the IRE1α pathway in podocytes and may play a cytoprotective role in glomerular diseases.

Keywords: Autophagy; Collagen IV; ERphagy; Endoplasmic reticulum stress; Reticulon-3; Sec23B

DOI: https://doi.org/10.1016/j.bbadis.2022.166391

Cell Stress Chaperones. 2022 Mar 16.

Endoplasmic reticulum-unfolded protein response pathway modulates the cellular response to mitochondrial proteotoxic stress.

Rajasri Sarkar, Kannan Boosi Narayana Rao, Mainak Pratim Jha, Koyeli Mapa.

Mitochondria and endoplasmic reticulum (ER) remain closely tethered by contact sites to maintain unhindered biosynthetic, metabolic, and signalling functions. Apart from its constituent proteins, contact sites localize ER-unfolded protein response (UPR) sensors like Ire1 and PERK, indicating the importance of ER-mitochondria communication during stress. In the mitochondrial sub-compartment-specific proteotoxic model of yeast, Saccharomyces cerevisiae, we show that an intact ER-UPR pathway is important in stress tolerance of mitochondrial intermembrane space (IMS) proteotoxic stress, while disrupting the pathway is beneficial during matrix stress. Deletion of IRE1 and HAC1 leads to accumulation of misfolding-prone proteins in mitochondrial IMS indicating the importance of intact ER-UPR pathway in enduring mitochondrial IMS proteotoxic stresses. Although localized proteotoxic stress within mitochondrial IMS does not induce ER-UPR, its artificial activation helps cells to better withstand the IMS proteotoxicity. Furthermore, overexpression of individual components of ER-mitochondria contact sites is found to be beneficial for general mitochondrial proteotoxic stress, in an Ire1-Hac1-independent manner.

Keywords: ER stress; ER-mitochondria contact sites; Mito-UPR; Protein homeostasis; Proteotoxic stress; Unfolded protein response

DOI: https://doi.org/10.1007/s12192-022-01264-2

J Hepatol. 2022 Mar 12. pii: S0168-8278(22)00140-4. [Epub ahead of print]

Role of XBP1 in regulating the progression of non-alcoholic steatohepatitis.

Qi Wang, Haoming Zhou, Qingfa Bu, Song Wei, Lei Li, Jinren Zhou, Shun Zhou, Wantong Su, Mu Liu, Zheng Liu, Mingming Wang, Ling Lu.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is associated with the dysregulation of lipid metabolism and hepatic inflammation. The mechanism underlying NASH is unclear. We aim to investigate the role of X-box binding protein-1 (XBP1) in the progression of NASH.
METHODS: Human liver tissues obtained from patients with NASH and control group were used to assess XBP1 expression. NASH models were developed in hepatocyte-specific Xbp1 knockout (Xbp1ΔHep), macrophage specific Xbp1 knockout (Xbp1ΔMϕ), macrophage-specific Nlrp3 knockout, and wild-type (Xbp1FL/FL or Nlrp3FL/FL) mice fed with high-fat diet for 26 weeks or methionine/choline deficient diet for 6 weeks.
RESULTS: The expression of XBP1 was significantly upregulated in the liver samples from NASH patients. Hepatocyte-specific Xbp1 deficiency inhibited the development of steatohepatitis in the mice fed with the high-fat or methionine/choline deficient diets. Meanwhile, macrophage specific Xbp1 knockout mice developed less severe steatohepatitis and fibrosis than wild-type Xbp1FL/FL mice in response to the high-fat or methionine/choline deficient diets. Macrophage-specific Xbp1 knockout mice showed M2 anti-inflammatory polarization. Xbp1 deleted macrophages reduced steatohepatitis through decreased expression of NLRP3 and secretion of pro-inflammatory cytokines, which mediate M2 macrophage polarization in macrophage-specific Xbp1 knockout mice. Steatohepatitis was less severe in macrophage-specific Nlrp3 knockout mice than in wild-type Nlrp3FL/FL mice. Xbp1 deleted macrophages prevented the hepatic stellate cells activation through decreased expression of TGF-β1. Less fibrotic changes were observed in macrophage-specific Xbp1 knockout mice than in the wild-type Xbp1FL/FL mice. Inhibition of XBP1 suppressed the development of NASH.
CONCLUSION: XBP1 regulates the development of NASH. XBP1 inhibitors protect against steatohepatitis. XBP1 thus is a potential target for the treatment of NASH.
LAY SUMMARY: XBP1 is a distinct basic-region leucine zipper transcription factor whose dynamic form is dominated by splicing response upon breakdown by homeostasis in the endoplasmic reticulum and activation of the unfolded protein response. Our study demonstrated that XBP1 is upregulated in liver tissues of patients with NASH. Conditional knockout of Xbp1 in the hepatocytes resulted in decreased lipid accumulation in mice. Genetic specific deletion of Xbp1 in macrophages ameliorated nutritional steatohepatitis and fibrosis in mice by reducing the secretion of pro-inflammatory cytokine, increasing M2 macrophage polarization, and decreasing TGF-β1 expression. Pharmacological inhibition of XBP1 protects against steatohepatitis and fibrosis, highlighting a promising strategy for NASH therapy.

Keywords: XBP1; hepatic stellate cells; hepatocytes; macrophages; non-alcoholic steatohepatitis

DOI: https://doi.org/10.1016/j.jhep.2022.02.031

Brain. 2021 Nov 23. pii: awab423. [Epub ahead of print]

Antisense therapies in neurological diseases.

Jean-Baptiste Brunet de Courssou, Alexandra Durr, David Adams, Jean-Christophe Corvol, Louise-Laure Mariani.

Advances in targeted regulation of gene expression allowed new therapeutic approaches for monogenic neurological diseases. Molecular diagnosis has paved the way to personalized medicine targeting the pathogenic roots: DNA or its RNA transcript. These antisense therapies rely on modified nucleotides sequences (single-strand DNA or RNA, both belonging to the antisense oligonucleotides family, or double-strand interfering RNA) to act specifically on pathogenic target nucleic acids, thanks to complementary base pairing. Depending on the type of molecule, chemical modifications and target, base pairing will lead alternatively to splicing modifications of primary transcript RNA or transient messenger RNA degradation or non-translation. The key to success for neurodegenerative diseases also depends on the ability to reach target cells. The most advanced antisense therapies under development in neurological disorders are presented here, at the clinical stage of development, either at phase 3 or market authorization stage, such as in spinal amyotrophy, Duchenne muscular dystrophy, transthyretin-related hereditary amyloidosis, porphyria and amyotrophic lateral sclerosis; or in earlier clinical phase 1 B, for Huntington disease, synucleinopathies and tauopathies. We also discuss antisense therapies at the preclinical stage, such as in some tauopathies, spinocerebellar ataxias or other rare neurological disorders. Each subtype of antisense therapy, antisense oligonucleotides or interfering RNA, has proved target engagement or even clinical efficacy in patients; undisputable recent advances for severe and previously untreatable neurological disorders. Antisense therapies show great promise, but many unknowns remain. Expanding the initial successes achieved in orphan or rare diseases to other disorders will be the next challenge, as shown by the recent failure in Huntington disease or due to long-term preclinical toxicity in multiple system atrophy and cystic fibrosis. This will be critical in the perspective of new planned applications to premanifest mutation carriers, or other non-genetic degenerative disorders such as multiple system atrophy or Parkinson disease.

Keywords: DNA; RNA interference; RNA silencing; antisense oligonucleotides; splicing

DOI: https://doi.org/10.1093/brain/awab423

Front Immunol. 2022 ;13 854730

Advances of DNA Damage Repair-Related Drugs and Combination With Immunotherapy in Tumor Treatment.

Yumin Wang, Meihan Duan, Zhouying Peng, Ruohao Fan, Yuxiang He, Hua Zhang, Wei Xiong, Weihong Jiang.

Cancer therapy has been an important and popular area in cancer research. With medical technology developing, the appearance of various targeted drugs and immunotherapy offer more choices to cancer treatment. With the increase in drug use, people have found more and more cases in which tumors are resistant to DNA damage repair (DDR)-based drugs. Recently, the concept of combination therapy has been brought up in cancer research. It takes advantages of combining two or more therapies with different mechanisms, aiming to benefit from the synergistic effects and finally rescue patients irresponsive to single therapies. Combination therapy has the potential to improve current treatment of refractory and drug-resistant tumors. Among the methods used in combination therapy, DDR is one of the most popular methods. Recent studies have shown that combined application of DDR-related drugs and immunotherapies significantly improve the therapeutic outcomes of malignant tumors, especially solid tumors.

Keywords: DNA damage; DNA repair; combination; immunotherapy; tumor treatment

DOI: https://doi.org/10.3389/fimmu.2022.854730