Deficiency in the autophagy modulator Dram1 exacerbates pyroptotic cell death of Mycobacteria-infected macrophages

Zhang, Rui; Varela, Mónica; Forn-Cuní, Gabriel; Torraca, Vincenzo; Vaart, Michiel van der; Meijer, Annemarie H.

doi:10.1101/599266

Cited by 10 publications

(26 citation statements)

References 71 publications

(69 reference statements)

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“…Moreover, we found that DRAM1 was involved in maintaining normal organization of the Golgi apparatus, suggesting that DRAM1 plays a role in Golgi functions 15 . It was recently reported that acidification of mycobacterium marinum (Mm)-containing vesicles was strongly reduced in DRAM1 mutants in tuberculosis (TB) model 16 . In the current study, we found that DRAM1 was decreased in NSCLC and negatively correlated with EGFR levels.…”

Section: Introductionmentioning

confidence: 99%

DRAM1 plays a tumor suppressor role in NSCLC cells by promoting lysosomal degradation of EGFR

et al. 2020

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Lung cancer is the leading cause of cancer-associated mortality worldwide. DNA damage-regulated autophagy modulator 1 (DRAM1) plays an important roles in autophagy and tumor progression. However, the mechanisms by which DRAM1 inhibits tumor growth are not fully understood. Here, we report that DRAM1 was decreased in nonsmall-cell lung carcinoma (NSCLC) and was associated with poor prognosis. We confirmed that DRAM1 inhibited the growth, migration, and invasion of NSCLC cells in vitro. Furthermore, overexpression of DRAM1 suppressed xenografted NSCLC tumors in vivo. DRAM1 increased EGFR endocytosis and lysosomal degradation, downregulating EGFR signaling pathway. On one side, DRAM1 interacted with EPS15 to promote EGFR endocytosis, as evidence by the results of proximity labeling followed by proteomics; on the other, DRAM1 recruited V-ATP6V1 subunit to lysosomes, thereby increasing the assemble of the V-ATPase complex, resulting in decreased lysosomal pH and increased activation of lysosomal proteases. These two actions of DRAM1 results in acceleration of EGFR degradation. In summary, these in vitro and in vivo studies uncover a novel mechanism through which DRAM1 suppresses oncogenic properties of NSCLC by regulating EGFR trafficking and degradation and highlights the potential value of DRAM1 as a prognostic biomarker in lung cancers.

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Section: Introductionmentioning

confidence: 99%

DRAM1 plays a tumor suppressor role in NSCLC cells by promoting lysosomal degradation of EGFR

et al. 2020

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“…In order to verify the results obtained using morpholino-mediated knockdown, we studied S. Typhimurium infection in a recently established dram1 mutant line (Zhang et al, 2020). We infected dram1 -/-and dram1 +/+ embryos with S. Typhimurium ( Figure 3A) and observed that dram1-/hosts showed increased mortality during S. Typhimurium infection as compared to dram1+/+ controls ( Figure 3B).…”

Section: Dram1 Mutation Recapitulates the Infection Phenotype Of Drammentioning

confidence: 87%

“…Similarly, induction of the zebrafish homolog of DRAM1 ( dram1 ) by Mycobacterium marinum infection relies on the TLR adaptor molecule MyD88 (van der Vaart et al, 2014). M. marinum -infected zebrafish embryos develop a tuberculosis-like disease and we have shown that Dram1 plays a host protective role in this model (van der Vaart et al ., 2014; Meijer and van der Vaart, 2014; Zhang et al ., 2020). Specifically, we found that knockdown of dram1 strongly reduces the co-localization of Lc3 with M. marinum , whereas overexpression increases Lc3- M. marinum co-localization in a manner dependent on the selective autophagy receptor p62 (Meijer and van der Vaart, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, we found that knockdown of dram1 strongly reduces the co-localization of Lc3 with M. marinum , whereas overexpression increases Lc3- M. marinum co-localization in a manner dependent on the selective autophagy receptor p62 (Meijer and van der Vaart, 2014). Additionally, we observed that in dram1 -/-CRISPR mutant zebrafish, not only Lc3 co-localization but also the acidification of M. marinum- containing vesicles was reduced (Zhang et al ., 2020). Failing to contain the intracellular infection, macrophages in dram1-/- zebrafish succumbed to pyroptotic cell death (Zhang et al ., 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, we observed that in dram1 -/-CRISPR mutant zebrafish, not only Lc3 co-localization but also the acidification of M. marinum- containing vesicles was reduced (Zhang et al ., 2020). Failing to contain the intracellular infection, macrophages in dram1-/- zebrafish succumbed to pyroptotic cell death (Zhang et al ., 2020).…”

Section: Introductionmentioning

confidence: 99%

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Dram1 confers resistance toSalmonellainfection

Masud

Zhang

et al. 2021

Preprint

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Dram1 is a stress and infection inducible autophagy modulator that functions downstream of transcription factors p53 and NFκB. Using a zebrafish embryo infection model, we have previously shown that Dram1 provides protection against the intracellular pathogen Mycobacterium marinum by promoting the p62-dependent xenophagy of bacteria that have escaped into the cytosol. However, the possible interplay between Dram1 and other anti-bacterial autophagic mechanisms remains unknown. Recently, LC3-associated phagocytosis (LAP) has emerged as an important host defense mechanism that requires components of the autophagy machinery and targets bacteria directly in phagosomes. Our previous work established LAP as the main autophagic mechanism by which macrophages restrict growth of Salmonella Typhimurium in a systemically infected zebrafish host. We therefore employed this infection model to investigate the possible role of Dram1 in LAP. Morpholino knockdown or CRISPR/Cas9-mediated mutation of Dram1 led to reduced host survival and increased bacterial burden during S. Typhimurium infections. In contrast, overexpression of dram1 by mRNA injection curtailed Salmonella replication and reduced mortality of the infected host. During the early response to infection, GFP-Lc3 levels in transgenic zebrafish larvae correlated with the dram1 expression level, showing over two-fold reduction of GFP-Lc3-Salmonella association in dram1 knockdown or mutant embryos and an approximately 30% increase by dram1 overexpression. Since LAP is known to require the activity of the phagosomal NADPH oxidase, we used a Salmonella biosensor strain to detect bacterial exposure to reactive oxygen species (ROS) and found that the ROS response was largely abolished in the absence of dram1. Together, these results demonstrate the host protective role of Dram1 during S. Typhimurium infection and suggest a functional link between Dram1 and the induction of LAP.

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Metal‐Free Atom Transfer Radical Polymerization of PVDF‐Based Block Copolymers Catalyzed by Organic Photoredox Catalysts

Altomare¹,

Loos²

2023

Macro Chemistry & Physics

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Front Cover: In article 2200259 by Katja Loos and Aldo Altomare, the light‐catalyzed atom transfer radical polymerization (ATRP) of PVDF‐based block copolymers with methyl methacrylate using five different organic photoredox catalysts (OPRC) is reported. The authors prove how the three OPRC operating through an oxidative quenching pathway offer a good control over the process. They also achieve successful chain‐extension and external temporal control through light ON‐light OFF process. Cover design by Dina Maniar.

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Deficiency in the autophagy modulator Dram1 exacerbates pyroptotic cell death of Mycobacteria-infected macrophages

Cited by 10 publications

References 71 publications

DRAM1 plays a tumor suppressor role in NSCLC cells by promoting lysosomal degradation of EGFR

DRAM1 plays a tumor suppressor role in NSCLC cells by promoting lysosomal degradation of EGFR

Dram1 confers resistance toSalmonellainfection

Metal‐Free Atom Transfer Radical Polymerization of PVDF‐Based Block Copolymers Catalyzed by Organic Photoredox Catalysts

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