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Identification of C. elegans ASNA-1 domains and tissue requirements that differentially influence platinum
Dorota Raj1, Agnieszka Podraza-Farhanieh1, Pablo Gallego2
1Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Abstract:
ASNA1 plays an essential role in cisplatin chemotherapy response, type 2 diabetes, and heart disease. It is also an important biomarker in the treatment response of many diseases. Biochemically, ASNA1 has two mutually exclusive redox-modulated roles: a tail-anchored protein (TAP) targeting function in the reduced state and a holdase/chaperone function in the oxidized state. Assigning biochemical roles of mammalian ASNA1 to biomedical functions is crucial for successful therapy development. Our previous work showed the relevance of the C. elegans ASNA-1 homolog in modeling cisplatin response and insulin secretion. Here we analyzed two-point mutants in highly conserved residues in C. elegans ASNA-1 and determined their importance in separating the cisplatin response function from its roles in insulin secretion. asna-1(ΔHis164) and asna-1(A63V) point mutants, which both preferentially exist in the oxidized state, displayed cisplatin sensitivity phenotype as well as TAP insertion defect but not an insulin secretion defect. Further, using targeted depletion we analyzed the tissue requirements of asna-1 for C. elegans growth and development. Somatic depletion of ASNA-1 as well as simultaneous depletion of ASNA-1 in neurons and intestines resulted in an L1 arrest. We concluded that, targeting single residues in ASNA-1 affecting Switch I/Switch II domain function, in comparison to complete knockdown counteracted cisplatin resistance without jeopardizing other important biological functions. Taken together, our study shows that effects on health caused by ASNA1 mutations can have different biochemical bases.
Insights
Targeting specific ASNA1 mutations can improve cisplatin chemotherapy response without harming essential biological functions. This research distinguishes ASNA1
Area of Science:
- Molecular Biology
- Biochemistry
- Genetics
Background:
- ASNA1 is crucial for chemotherapy response, diabetes, and heart disease, acting as a biomarker.
- ASNA1 has dual redox-modulated roles: tail-anchored protein (TAP) targeting (reduced) and holdase/chaperone (oxidized).
- Understanding ASNA1's biochemical roles is key for therapeutic development.
Purpose of the Study:
- To analyze two-point mutants in C. elegans ASNA-1 to separate cisplatin response from insulin secretion roles.
- To investigate the tissue-specific requirements of ASNA-1 for growth and development.
Main Methods:
- Analysis of two-point mutants (asna-1(ΔHis164) and asna-1(A63V)) in C. elegans.
- Assessment of cisplatin sensitivity, TAP insertion, and insulin secretion.
- Targeted depletion of ASNA-1 in specific tissues to study developmental roles.
Main Results:
- Mutants favoring the oxidized state (asna-1(ΔHis164), asna-1(A63V)) showed cisplatin sensitivity and TAP insertion defects but no insulin secretion defect.
- Somatic or neuronal/intestinal depletion of ASNA-1 led to L1 arrest, indicating essential roles in development.
- Targeting single residues affecting Switch I/II domain function counteracted cisplatin resistance without compromising other biological functions.
Conclusions:
- Specific ASNA1 residue modifications can decouple cisplatin resistance from essential biological functions.
- This study provides a basis for developing targeted therapies by modulating ASNA1's biochemical activities.
- ASNA1 mutations can have diverse biochemical underpinnings for their health effects.
