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Alternative redox f...
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Raj, DorotaGothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery
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Alternative redox forms of ASNA-1 separate insulin signaling from tail-anchored protein targeting and cisplatin resistance in C. elegans
- Artikel/kapitelEngelska2021
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2021-04-21
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Springer Science and Business Media LLC,2021
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LIBRIS-ID:oai:gup.ub.gu.se/308510
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https://gup.ub.gu.se/publication/308510URI
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https://doi.org/10.1038/s41598-021-88085-yDOI
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https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-182496URI
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Cisplatin is a frontlinecancer therapeutic, but intrinsic or acquired resistance is common. We previouslyshowed that cisplatin sensitivity can be achieved by inactivation ofASNA-1/TRC40in mammalian cancer cells and inCaenorhabditiselegans. ASNA-1 has two more conservedfunctions: in promoting tail-anchored protein (TAP) targeting to theendoplasmicreticulum membrane and in promoting insulin secretion. However, the relationbetween its different functions has remained unknown. Here, we show that ASNA-1exists in two redox states that promote TAP-targeting and insulin secretion separately.The reduced state is the one required for cisplatin resistance: an ASNA-1 point mutant, in which the protein preferentially was found in the oxidized state, was sensitive to cisplatin and defective for TAP targeting but had no insulin secretion defect. The same was true for mutants inwrb-1,which we identifyas theC. eleganshomolog of WRB, the ASNA1/TRC40 receptor. Finally,we uncover a previously unknown action of cisplatin induced reactive oxygen species: cisplatin inducedROSdrives ASNA-1 into the oxidized form, andselectively prevents an ASNA-1-dependent TAP substrate from reaching the endoplasmicreticulum. Our work suggests that ASNA-1 acts as aredox-sensitive target forcisplatin cytotoxicity and that cisplatin resistance is likely mediated by ASNA-1-dependent TAP substrates. Treatments that promote an oxidizing tumor environmentshould be explored as possible means to combatcisplatin resistance. © 2021, The Author(s).
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Billing, Ola,1981-Umeå universitet,Kirurgi(Swepub:umu)olabig00
(författare)
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Podraza-Farhanieh, Agnieszka,1991Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery(Swepub:gu)xpodag
(författare)
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Kraish, BasharGothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery
(författare)
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Hemmingsson, Oskar,1975-Umeå universitet,Kirurgi(Swepub:umu)osrhen96
(författare)
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Kao, GautamGothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery(Swepub:gu)xkaoga
(författare)
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Naredi, Peter,1955Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery(Swepub:gu)xnarpe
(författare)
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Göteborgs universitetInstitutionen för kliniska vetenskaper, Avdelningen för kirurgi
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Ingår i:Scientific Reports: Springer Science and Business Media LLC11:12045-2322
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