LCDR maintains the integrity of lysosomal membrane by hnRNP K-stabilized LAPTM5 transcript and promotes cell survival
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA727295 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14421423_1.fastq.gz | Fastqsanger.gz | |||
| SRR14421423_2.fastq.gz | Fastqsanger.gz | |||
| SRR14421424_1.fastq.gz | Fastqsanger.gz | |||
| SRR14421424_2.fastq.gz | Fastqsanger.gz | |||
| SRR14421425_1.fastq.gz | Fastqsanger.gz |
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Project description:Lysosome plays important roles in cellular homeostasis and its dysregulation is associated with cancer. However, the regulation and underlying mechanism of lysosome in cancer survival remain incompletely understood. Here, we reveal a role for a histone acetylation-regulated long non-coding RNA termed as lysosome cell death regulator (LCDR) in lung cancer cell survival, knockdown of which promotes apoptosis. Mechanistically, LCDR binds to heterogenous nuclear ribonucleoprotein K (hnRNP K) to regulate the stability of lysosomal-associated protein transmembrane 5 (LAPTM5) transcript that maintain integrity of lysosomal membrane. Consequently, knockdown of LCDR, hnRNP K or LAPTM5 promotes lysosomal membrane permeabilization and lysosomal cell death-mediated apoptosis. LAPTM5 overexpression or cathepsin B inhibitor partially restores the effects of this axis on lysosomal cell death. Clinically, LCDR/hnRNP K/LAPTM5 are upregulated in lung cancer tissues and coexpression of this axis shows the increased diagnostic value for lung cancer. These findings shed light on LCDR/hnRNP K/LAPTM5 as potential therapeutic targets and targeting lysosome is a promising strategy in cancer treatment.
2021-05-05 | GSE173849 | GEO
Project description:Lysosome plays important roles in cellular homeostasis, and its dysregulation contributes to tumor growth and survival. However, the understanding of regulation and the underlying mechanism of lysosome in cancer survival is incomplete. Here, we reveal a role for a histone acetylation-regulated long noncoding RNA termed lysosome cell death regulator (LCDR) in lung cancer cell survival, in which its knockdown promotes apoptosis. Mechanistically, LCDR binds to heterogenous nuclear ribonucleoprotein K (hnRNP K) to regulate the stability of the lysosomal-associated protein transmembrane 5 (LAPTM5) transcript that maintains the integrity of the lysosomal membrane. Knockdown of LCDR, hnRNP K, or LAPTM5 promotes lysosomal membrane permeabilization and lysosomal cell death, thus consequently resulting in apoptosis. LAPTM5 overexpression or cathepsin B inhibitor partially restores the effects of this axis on lysosomal cell death in vitro and in vivo. Similarly, targeting LCDR significantly decreased tumor growth of patient-derived xenografts of lung adenocarcinoma (LUAD) and had significant cell death using nanoparticles (NPs)-mediated systematic short interfering RNA delivery. Moreover, LCDR/hnRNP K/LAPTM5 are up-regulated in LUAD tissues, and coexpression of this axis shows the increased diagnostic value for LUAD. Collectively, we identified a long noncoding RNA that regulates lysosome function at the posttranscriptional level. These findings shed light on LCDR/hnRNP K/LAPTM5 as potential therapeutic targets, and targeting lysosome is a promising strategy in cancer treatment.
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Project description:The P-TEFb complex promotes transcription elongation by releasing paused RNA polymerase II. P-TEFb itself is known to be inactivated through binding to the non-coding RNA 7SK but there is only limited information about mechanisms regulating their association. Here, we show that cells deficient in the RNA-binding protein hnRNP R, a known 7SK interactor, exhibit increased transcription due to phosphorylation of RNA polymerase II. Intriguingly, loss of hnRNP R promotes the release of P-TEFb from 7SK, accompanied by enhanced hnRNP A1 binding to 7SK. Additionally, we found that hnRNP R interacts with BRD4, and that hnRNP R depletion increases BRD4 binding to the P-TEFb component CDK9. Finally, CDK9 is stabilized upon loss of hnRNP R and its association with Cyclin K is enhanced. Together, our results indicate that hnRNP R negatively regulates transcription by modulating the activity and stability of the P-TEFb complex, exemplifying the multimodal regulation of P-TEFb by an RNA-binding protein.
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Project description:Lysosomal integrity suppresses TIR-1/SARM1 aggregation to restrain toxic propagation of p38 innate immunity
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Project description:Neurons critically rely on the functions of RNA-binding proteins to maintain their polarity and resistance to neurotoxic stresses. HnRNP R has a diverse range of post-transcriptional regulatory functions and is important for neuronal development by regulating axon growth. Hnrnpr pre-mRNA undergoes alternative splicing to produce transcripts encoding two isoforms: a full-length protein and a shorter form lacking the N-terminal acidic domain. While the neuronal defects produced by total hnRNP R depletion have been investigated before, the individual functions of each hnRNP R isoforms are unknown. We generated a Hnrnpr knockout mouse (Hnrnprtm1a/tm1a) showing selective loss of the full-length hnRNP R isoform. Motoneurons cultured from Hnrnprtm1a/tm1a mice did not show any axonal growth defects. However, they show an accumulation of double-strand breaks and an impaired DNA damage response. Proteomic analysis of the hnRNP R interactome revealed the multifunctional protein Yb1 as a top interactor. Yb1 depleted motoneurons also exhibit defects in DNA damage repair. We show that Yb1 is recruited to chromatin upon DNA damage, a mechanism that is dependent on full-length hnRNP R. Our findings thus suggest a novel role of hnRNP R in maintaining genomic integrity and highlight the function of its Nterminal acidic domain in this context.
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Project description:Neurons critically rely on the functions of RNA-binding proteins to maintain their polarity and resistance to neurotoxic stresses. HnRNP R has a diverse range of post-transcriptional regulatory functions and is important for neuronal development by regulating axon growth. Hnrnpr pre-mRNA undergoes alternative splicing to produce transcripts encoding two protein isoforms: a full-length protein and a shorter form lacking the N-terminal acidic domain. While the neuronal defects produced by total hnRNP R depletion have been investigated before, the individual functions of each hnRNP R isoforms are unknown. We generated a Hnrnpr knockout mouse (Hnrnprtm1a/tm1a) showing selective loss of the full-length hnRNP R isoform. Motoneurons cultured from Hnrnprtm1a/tm1a mice did not show any axonal growth defects. However, they show an accumulation of double-strand breaks and an impaired DNA damage response. Proteomic analysis of the hnRNP R interactome revealed the multifunctional Y-box binding protein 1 (Yb1) as a top interactor. Yb1 depleted motoneurons also exhibit defects in DNA ´damage repair. We show that Yb1 is recruited to chromatin upon DNA damage, a mechanism that is dependent on full length hnRNP R. Our findings thus suggest a novel role of hnRNP R in maintaining genomic integrity and highlight the function of its N-terminal acidic domain in this context.
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