CRISPR screens identify novel regulators of cFLIP dependency and ligand-independent, TRAIL-R1-mediated cell death

Kuehnle, Neil; Osborne, Scout Mask; Liang, Zhanfeng; Manzano, Mark; Gottwein, Eva

doi:10.1038/s41418-023-01133-0

Cited by 3 publications

(1 citation statement)

References 91 publications

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“…Recent studies have shown that ufmylation is implicated in human diseases, such as hematopoietic diseases (16)(17)(18), heart diseases (19), diabetes (20), intestinal exocrine diseases (21), neuronal diseases (22)(23)(24)(25), and cancer (9,12). At the cellular level, ufmylation regulates endoplasmic reticulum (ER) stress (11,26,27), ER-phagy (6,28,29), ribosome-and translocationassociated quality control (14,(30)(31)(32)(33), genomic integrity (8,15), and cell development and death (15,(34)(35)(36). However, virtually nothing is known about its functions and regulation in cellular protein trafficking.…”

Section: Introductionmentioning

confidence: 99%

The ufmylation cascade controls COPII recruitment, anterograde transport, and sorting of nascent GPCRs at ER

Xu,

Huang,

Bryant

et al. 2024

Sci. Adv.

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Ufmylation is implicated in multiple cellular processes, but little is known about its functions and regulation in protein trafficking. Here, we demonstrate that the genetic depletion of core components of the ufmylation cascade, including ubiquitin-fold modifier 1 (UFM1), UFM1 activation enzyme 5, UFM1-specific ligase 1 (UFL1), UFM1-specific protease 2, and UFM1-binding protein 1 (UFBP1) each markedly inhibits the endoplasmic reticulum (ER)–Golgi transport, surface delivery, and recruitment to COPII vesicles of a subset of G protein–coupled receptors (GPCRs) and UFBP1’s function partially relies on UFM1 conjugation. We also show that UFBP1 and UFL1 interact with GPCRs and UFBP1 localizes at COPII vesicles coated with specific Sec24 isoforms. Furthermore, the UFBP1/UFL1-binding domain identified in the receptors effectively converts non-GPCR protein transport into the ufmylation-dependent pathway. Collectively, these data reveal important functions for the ufmylation system in GPCR recruitment to COPII vesicles, biosynthetic transport, and sorting at ER via UFBP1 ufmylation and interaction directly.

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Section: Introductionmentioning

confidence: 99%

The ufmylation cascade controls COPII recruitment, anterograde transport, and sorting of nascent GPCRs at ER

Xu,

Huang,

Bryant

et al. 2024

Sci. Adv.

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Let’s make it personal: CRISPR tools in manipulating cell death pathways for cancer treatment

Bayat,

Nahand

2024

Cell Biol Toxicol

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Advancements in the CRISPR technology, a game-changer in experimental research, have revolutionized various fields of life sciences and more profoundly, cancer research. Cell death pathways are among the most deregulated in cancer cells and are considered as critical aspects in cancer development. Through decades, our knowledge of the mechanisms orchestrating programmed cellular death has increased substantially, attributed to the revolution of cutting-edge technologies. The heroic appearance of CRISPR systems have expanded the available screening platform and genome engineering toolbox to detect mutations and create precise genome edits. In that context, the precise ability of this system for identification and targeting of mutations in cell death signaling pathways that result in cancer development and therapy resistance is an auspicious choice to transform and accelerate the individualized cancer therapy. The concept of personalized cancer therapy stands on the identification of molecular characterization of the individual tumor and its microenvironment in order to provide a precise treatment with the highest possible outcome and minimum toxicity. This study explored the potential of CRISPR technology in precision cancer treatment by identifying and targeting specific cell death pathways. It showed the promise of CRISPR in finding key components and mutations involved in programmed cell death, making it a potential tool for targeted cancer therapy. However, this study also highlighted the challenges and limitations that need to be addressed in future research to fully realize the potential of CRISPR in cancer treatment. Graphical abstract Current application of CRISPR system in cancer therapy through a glance. A choosing the appropriate biological model for screening in vitro (using established cell lines, animal derived tumor cells, human derived tumor cells, stem cells or T cells), in vivo (using animal models which can harbor human derived tumor), or ex vivo (human/animal-derived organoids). B preparation of CRISPR gRNA library. C experimental design of CRISPR screening, identification of the desired gRNAs or phenotypic response. D CRISPR-Cas targeting of the identified targets, with Cas9 gene editing system (Knockout, base editing, prime editing), RNA modulation (modulation of RNA splicing, RNA base editing, RNA interference), and epigenomic edits and CRISPR interference/activation using dead Cas9 (dCas9) (Bock et al. 2022b)

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A JAGN1-associated severe congenital neutropenia zebrafish model revealed an altered G-CSFR signaling and UPR activation

Doll,

Welte,

Skokowa

et al. 2024

Blood Advances

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A variety of autosomal recessive mutations in the JAGN1 gene cause severe congenital neutropenia (CN). However, the underlying pathomechanism remains poorly understood, mainly due to the limited availability of primary hematopoietic stem cells from JAGN1-CN patients and the absence of animal models. In this study, we aimed to address these limitations by establishing a zebrafish model of JAGN1-CN. We found two paralogs of the human JAGN1 gene, jagn1a and jagn1b, which play distinct roles during zebrafish hematopoiesis. Using various approaches such as morpholino-based knockdown, CRISPR/Cas9-based gene-editing, and misexpression of a jagn1b harboring a specific human mutation, we successfully developed neutropenia while leaving other hematopoietic lineages unaffected. Further analysis of our model revealed significant upregulation of apoptosis and genes involved in unfolded protein response (UPR). However, neither UPR nor apoptosis is the primary mechanism leading to neutropenia in zebrafish. Instead, Jagn1b has a critical role in G-CSFR signaling and steady-state granulopoiesis, shedding light on the pathogenesis of neutropenia associated with JAGN1 mutations. The establishment of a zebrafish model for JAGN1-CN represents a significant advancement in understanding the specific pathological pathways underlying the disease. This model provides a valuable in vivo tool for further investigation and exploration of potential therapeutic strategies.

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CRISPR screens identify novel regulators of cFLIP dependency and ligand-independent, TRAIL-R1-mediated cell death

Cited by 3 publications

References 91 publications

The ufmylation cascade controls COPII recruitment, anterograde transport, and sorting of nascent GPCRs at ER

The ufmylation cascade controls COPII recruitment, anterograde transport, and sorting of nascent GPCRs at ER

Let’s make it personal: CRISPR tools in manipulating cell death pathways for cancer treatment

A JAGN1-associated severe congenital neutropenia zebrafish model revealed an altered G-CSFR signaling and UPR activation

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