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PRTN3 suppresses cytotoxic immune-cell activation and antitumoral immunity through proteolytic cleavage of CXCL9 in KRAS mutant lung adenocarcinoma

ABSTRACT: PRTN3 suppresses cytotoxic immune-cell activation and antitumoral immunity through proteolytic cleavage of CXCL9 in KRAS mutant lung adenocarcinoma

PROVIDER: PRJNA1132973 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29735634.fastq.gz	Fastqsanger.gz
	SRR29735635.fastq.gz	Fastqsanger.gz
	SRR29735636.fastq.gz	Fastqsanger.gz
	SRR29735637.fastq.gz	Fastqsanger.gz

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PRTN3 suppresses cytotoxic immune-cell activation and antitumoral immunity through proteolytic cleavage of CXCL9 in KRAS mutant lung adenocarcinoma

Project description:The intratumoral activity of chemokine system has important roles in cancer immunotherapy strategies.One of the mechanisms of immune checkpoint blocking (ICB)resistance may be the dysfunction of chemokine signaling. Here, we first report that KRAS mutation in LUAD cells up-regulates the expression of protease 3 (PRTN3), that inhibits cytotoxic immune cell activation in the tumor microenvironment by inhibiting the CXCL9/CXCR3 axis, providing an unconventional mechanism for tumor immune escape. Further mechanism studies demonstrated that PRTN3 was up-regulated by c-Myc transcription and secreted into the tumor microenvironment, where CXCL9 was inactivated by proteolysis, and finally result in inhibiting the activation of natural killer (NK) and CD8+ T cells. Meanwhile, samples from LUAD patients with high PRTN3 expression showed low CXCL9 activity. Furthermore, application of a hydrolysis-resistant CXCL9 protein (H-R CXCL9) effectively improves the immunomodulate effect in LUAD patient organoids. Importantly, PRTN3 knockdown increased the susceptibility of KRAS mutant cells to Anti-pd-1 therapy. Thus, we have identified a previously unknown tumor immune-suppressive mechanism and provided an immunotherapeutic target to improve the effectiveness of ICB therapy in KRAS mutant LUAD.

2024-07-13 | GSE271713 | GEO

Proteolytic cleavage by taspase1 and the regulation of the stability of MLL1

Project description:Chromosomal translocations of the Mixed-lineage leukemia 1 (MLL1) gene generate MLL-chimeras that drive pathogenesis of acute myeloid and lymphoid leukemia. The untranslocated MLL1 is a substrate for proteolytic cleavage by the endopeptidase, taspase1, however, the biological significance of MLL1 cleavage by this endopeptidase remains unclear. Here, we demonstrate that taspase1-dependent cleavage of MLL1 results in the destabilization of full-length MLL. Upon loss of taspase1, MLL1 association with chromatin is markedly increased due to the stabilization of its unprocessed version and this stabilization of the uncleaved MLL1 can result in the displacement of MLL-chimeras from chromatin in leukemic cells. Casein kinase II (CKII) phosphorylates MLL1 proximal to the taspase1 cleavage site, facilitating its cleavage, and pharmacological inhibition of CKII blocks taspase1-dependent MLL1 processing, increases MLL1 stability, and results in the displacement of the MLL-chimeras from chromatin. Furthermore, inhibition of CKII in MLL-AF9 mouse model of leukemia delayed leukemic progression in vivo. This study provides insights into the direct regulation of the stability of MLL1, which can be harnessed for targeted therapeutic approaches for the treatment of aggressive MLL leukemia.

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Intrauterine Botulinum Toxin A administration promotes thin endometrium regeneration in a manner dependent on regulatory effect of insulin-like growth factor-binding protein 3 on osteopontin proteolytic cleavage in mice

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Time-resolved analysis of proteolytic cleavage sites in Tau and fibrillar Tau.

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Time-resolved analysis of proteolytic cleavage sites in Malate dehydrogenase by Trypsin.

Project description:A proteolytic cleavage experiment was performed with the protein Malate dehydrogenase (MDH) and Trypsin protease, to identify early cleavage sites in MDH. Various concentrations of Trypsin (5,000, 10,000 and 100,000 x diluted) were tested and early timepoints taken to detect only few cleavage sites in order to identify the very first events of MDH proteolysis

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Phosphorylation-Regulated Cleavage of ETHYLENE INSENSITIVE2 Mediates Hormone Signaling from the Endoplasmic Reticulum to the Nucleus

Project description:Ethylene gas is essential for many developmental processes and stress responses in plants. ETHYLENE INSENSITIVE2 (EIN2), an NRAMP-homologous integral membrane protein, plays an essential role in ethylene signaling but its function remains enigmatic. Here we report that phosphorylation-regulated proteolytic processing of EIN2 triggers its endoplasmic reticulum (ER)-nucleus translocation, which is essential for hormone signaling and response in Arabidopsis. Without ethylene, or in hormone receptors mutants, ER-tethered EIN2 shows CTR1 kinase-dependent phosphorylation. Ethylene exposure triggers dephosphorylation and proteolytic cleavage, resulting in rapid nuclear translocation of a carboxyl-terminal EIN2 fragment (C’). Plants containing mutations that mimic EIN2 dephosphorylation, or inactivate CTR1, show constitutive cleavage and nuclear localization of EIN2-C’, and EIN3/EIL1-dependent activation of ethylene responses. These findings uncover a mechanism of subcellular communication whereby ethylene gas stimulates rapid phosphorylation-dependent cleavage and nuclear movement of the EIN2-C’ peptide, thus linking hormone perception and signaling components located in the ER with nuclear-localized transcriptional regulators.

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Transmembrane serine protease 2 and proteolytic activation of the epithelial sodium channel in mouse kidney: Effects of TMPRSS2 knockout

Project description:The appropriate regulation of the epithelial sodium channel (ENaC) in the aldosterone-sensitive distal nephron is required for sodium homeostasis and thereby for the long-term regulation of arterial blood pressure. A unique feature of ENaC is its activation by proteolytic cleavage. However, the relevant proteases involved in proteolytic ENaC activation in the kidney remain elusive. Here, we examined a potential role of transmembrane serine protease 2 (TMPRSS2). A mouse cortical collecting duct cell line (mCCDcl1) was used as a model system. We performed RNA-Seq transcriptome analysis of mCCDcl1 cells, which confirmed coexpression of Tmprss2 and all three ENaC subunits (Scnn1a, Scnn1b, Scnn1g) in this cell line. Importantly, high baseline expression of TMPRSS2 was detected in these cells without a stimulatory effect of aldosterone on its function or transcription. TMPRSS2 knockout in mCCDcl1 cells compromised γ-ENaC cleavage and reduced baseline and aldosterone-stimulated transepithelial short-circuit currents, which could be rescued by chymotrypsin. A compensatory transcriptional upregulation of other proteases was not observed. From these findings we conclude that TMPRSS2 is likely to contribute to proteolytic ENaC activation in the kidney.

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Transmembrane serine protease 2 and proteolytic activation of the epithelial sodium channel in mouse kidney: Late effects of aldosterone

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Transmembrane serine protease 2 and proteolytic activation of the epithelial sodium channel in mouse kidney: Early effects of aldosterone

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