The caspase-2 substrate p54nrb exhibits a multifaceted role in tumor cell death susceptibility via gene regulatory functions.
Madeleine EichlerUte DistlerUsman NasrullahAswini KrishnanManuel KaulichKoraljka HusnjakWolfgang EberhardtKrishnaraj RajalingamStefan TenzerJosef PfeilschifterGergely ImrePublished in: Cell death & disease (2022)
Caspase-2 represents an evolutionary conserved caspase, which plays a role in genotoxic stress-induced apoptosis, ageing-related metabolic changes, and in deleting aneuploid cells in tumors. Genetic deletion of caspase-2 leads to increased tumor susceptibility in vivo. The exact downstream signaling mechanism by which caspase-2 accomplishes its specific tumor suppressor functions is not clear. Caspase-2, uniquely among caspases, resides in the nucleus and other cellular compartments. In this study, we identify a nuclear caspase-2 specific substrate, p54nrb, which is selectively cleaved by caspase-2 at D422, leading to disruption of the C-terminal site, the putative DNA binding region of the protein. P54nrb is an RNA and DNA binding protein, which plays a role in RNA editing, transport, and transcriptional regulation of genes. Overexpression of p54nrb is observed in several human tumor types, such as cervix adenocarcinoma, melanoma, and colon carcinoma. In contrast, the loss of p54nrb in tumor cell lines leads to increased cell death susceptibility and striking decrease in tumorigenic potential. By employing high resolution quantitative proteomics, we demonstrate that the loss/cleavage of p54nrb results in altered expression of oncogenic genes, among which the downregulation of the tumorigenic protease cathepsin-Z and the anti-apoptotic gelsolin can be detected universally across three tumor cell types, including adenocarcinoma, melanoma and colon carcinoma. Finally, we demonstrate that p54nrb interacts with cathepsin-Z and gelsolin DNA, but not RNA. Taken together, this study uncovers a so far not understood mechanism of caspase-2 tumor suppressor function in human tumor cells.
Keyphrases
- cell death
- induced apoptosis
- endoplasmic reticulum stress
- cell cycle arrest
- signaling pathway
- oxidative stress
- dna binding
- binding protein
- high resolution
- transcription factor
- genome wide
- endothelial cells
- squamous cell carcinoma
- cell proliferation
- magnetic resonance
- poor prognosis
- mass spectrometry
- magnetic resonance imaging
- crispr cas
- single cell
- circulating tumor
- risk assessment
- gene expression
- single molecule
- stem cells
- dna methylation
- long non coding rna
- cell free
- pluripotent stem cells
- structural basis
- high speed