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MicroRNAs Affect Complement Regulator Expression and Mitochondrial Activity to Modulate Cell Resistance to
Yaron Hillman1, Mariya Mardamshina2, Metsada Pasmanik-Chor3
1Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Abstract:
MicroRNAs (miR) are small RNA molecules that shape the cell transcriptome and proteome through regulation of mRNA stability and translation. Here, we examined their function as determinants of cell resistance to complement-dependent cytotoxicity (CDC). To achieve this goal, we compared the expression of microRNAs between complement-resistant and -sensitive K562 leukemia, Raji lymphoma, and HCT-116 colorectal carcinoma cells. Global microRNA array analysis identified miR-150, miR-328, and miR-616 as regulators of CDC resistance. Inhibition of miR-150 reduced resistance, whereas inhibition of miR-328 or miR-616 enhanced cell resistance. Treatment of K562 cells with a sublytic dose of complement was shown to rapidly increase miR-150, miR-328, and miR-616 expression. Protein targets of these microRNAs were analyzed in K562 cells by mass spectrometry-based proteomics. Expression of the complement membrane regulatory proteins CD46 and CD59 was significantly enhanced after inhibition of miR-328 and miR-616. Enrichment of proteins of mitochondria, known target organelles in CDC, was observed after miR-150, miR-328, and miR-616 inhibition. In conclusion, miR-150, miR-328, and miR-616 regulate cell resistance to CDC by modifying the expression of the membrane complement regulators CD46 and CD59 and the response of the mitochondria to complement lytic attack. These microRNAs may be considered targets for intervention in complement-associated diseases and in anticancer, complement-based therapy.
Insights
MicroRNAs regulate resistance to complement-dependent cytotoxicity (CDC). Specific microRNAs (miR-150, miR-328, miR-616) impact cell survival by modulating complement regulators and mitochondrial response to CDC.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- MicroRNAs (miRNAs) are crucial regulators of gene expression, influencing cellular processes.
- Complement-dependent cytotoxicity (CDC) is a key immune mechanism targeting cells.
- Understanding miRNA roles in CDC resistance is vital for therapeutic development.
Purpose of the Study:
- To investigate the role of microRNAs in determining cellular resistance to complement-dependent cytotoxicity (CDC).
- To identify specific microRNAs that regulate cell sensitivity or resistance to CDC.
Main Methods:
- Comparative microRNA expression analysis between CDC-resistant and -sensitive cancer cell lines (K562, Raji, HCT-116).
- Global microRNA array profiling to identify key miRNA regulators.
- Inhibition of specific miRNAs to assess effects on CDC resistance.
- Mass spectrometry-based proteomics to identify protein targets of regulatory miRNAs.
Main Results:
- miR-150, miR-328, and miR-616 were identified as key regulators of CDC resistance.
- Inhibition of miR-150 decreased resistance, while inhibiting miR-328 or miR-616 increased resistance.
- Complement treatment rapidly upregulated miR-150, miR-328, and miR-616.
- miRNA inhibition affected expression of complement regulators CD46 and CD59.
- Mitochondrial protein enrichment was observed upon inhibition of these miRNAs, indicating altered response to complement attack.
Conclusions:
- miR-150, miR-328, and miR-616 are critical modulators of cellular resistance to CDC.
- These miRNAs influence CDC resistance by altering CD46 and CD59 expression and mitochondrial response.
- Targeting these microRNAs offers potential therapeutic strategies for complement-associated diseases and anti-cancer therapies.
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