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Alternative translation and retrotranslocation of cytosolic C3 that detects cytoinvasive bacteria

Complement C3 was originally regarded as a serum effector protein, although recent data has emerged suggesting that intracellular C3 can also regulate basic cellular processes. Despite the growing interest in intracellular C3 functions, the mechanism behind its generation has not been demonstrated....

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Autores principales: Kremlitzka, Mariann, Colineau, Lucie, Nowacka, Alicja A., Mohlin, Frida C., Wozniak, Katarzyna, Blom, Anna M., King, Ben C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9095555/
https://www.ncbi.nlm.nih.gov/pubmed/35546365
http://dx.doi.org/10.1007/s00018-022-04308-z
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author Kremlitzka, Mariann
Colineau, Lucie
Nowacka, Alicja A.
Mohlin, Frida C.
Wozniak, Katarzyna
Blom, Anna M.
King, Ben C.
author_facet Kremlitzka, Mariann
Colineau, Lucie
Nowacka, Alicja A.
Mohlin, Frida C.
Wozniak, Katarzyna
Blom, Anna M.
King, Ben C.
author_sort Kremlitzka, Mariann
collection PubMed
description Complement C3 was originally regarded as a serum effector protein, although recent data has emerged suggesting that intracellular C3 can also regulate basic cellular processes. Despite the growing interest in intracellular C3 functions, the mechanism behind its generation has not been demonstrated. In this study we show that C3 can be expressed from an alternative translational start site, resulting in C3 lacking the signal peptide, which is therefore translated in the cytosol. In contrast to the secreted form, alternatively translated cytosolic C3 is not glycosylated, is present mainly in a reduced state, and is turned over by the ubiquitin–proteasome system. C3 can also be retrotranslocated from the endoplasmic reticulum into the cytosol, structurally resembling secreted C3. Finally, we demonstrate that intracellular cytosolic C3 can opsonize invasive Staphylococcus aureus within epithelial cell, slowing vacuolar escape as well as impacting bacterial survival on subsequent exposure to phagocytes. Our work therefore reveals the existence and origin of intracellular, cytosolic C3, and demonstrates functions for cytosolic C3 in intracellular detection of cytoinvasive pathogens. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04308-z.
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spelling pubmed-90955552022-05-13 Alternative translation and retrotranslocation of cytosolic C3 that detects cytoinvasive bacteria Kremlitzka, Mariann Colineau, Lucie Nowacka, Alicja A. Mohlin, Frida C. Wozniak, Katarzyna Blom, Anna M. King, Ben C. Cell Mol Life Sci Original Article Complement C3 was originally regarded as a serum effector protein, although recent data has emerged suggesting that intracellular C3 can also regulate basic cellular processes. Despite the growing interest in intracellular C3 functions, the mechanism behind its generation has not been demonstrated. In this study we show that C3 can be expressed from an alternative translational start site, resulting in C3 lacking the signal peptide, which is therefore translated in the cytosol. In contrast to the secreted form, alternatively translated cytosolic C3 is not glycosylated, is present mainly in a reduced state, and is turned over by the ubiquitin–proteasome system. C3 can also be retrotranslocated from the endoplasmic reticulum into the cytosol, structurally resembling secreted C3. Finally, we demonstrate that intracellular cytosolic C3 can opsonize invasive Staphylococcus aureus within epithelial cell, slowing vacuolar escape as well as impacting bacterial survival on subsequent exposure to phagocytes. Our work therefore reveals the existence and origin of intracellular, cytosolic C3, and demonstrates functions for cytosolic C3 in intracellular detection of cytoinvasive pathogens. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00018-022-04308-z. Springer International Publishing 2022-05-11 2022 /pmc/articles/PMC9095555/ /pubmed/35546365 http://dx.doi.org/10.1007/s00018-022-04308-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Kremlitzka, Mariann
Colineau, Lucie
Nowacka, Alicja A.
Mohlin, Frida C.
Wozniak, Katarzyna
Blom, Anna M.
King, Ben C.
Alternative translation and retrotranslocation of cytosolic C3 that detects cytoinvasive bacteria
title Alternative translation and retrotranslocation of cytosolic C3 that detects cytoinvasive bacteria
title_full Alternative translation and retrotranslocation of cytosolic C3 that detects cytoinvasive bacteria
title_fullStr Alternative translation and retrotranslocation of cytosolic C3 that detects cytoinvasive bacteria
title_full_unstemmed Alternative translation and retrotranslocation of cytosolic C3 that detects cytoinvasive bacteria
title_short Alternative translation and retrotranslocation of cytosolic C3 that detects cytoinvasive bacteria
title_sort alternative translation and retrotranslocation of cytosolic c3 that detects cytoinvasive bacteria
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9095555/
https://www.ncbi.nlm.nih.gov/pubmed/35546365
http://dx.doi.org/10.1007/s00018-022-04308-z
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