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Knyazeva, A., Li, S., Corkery, D. P., Shankar, K., Herzog, L. K., Zhang, X., . . . Wu, Y.-W. (2024). A chemical inhibitor of IST1-CHMP1B interaction impairs endosomal recycling and induces noncanonical LC3 lipidation. Proceedings of the National Academy of Sciences of the United States of America, 121(17), Article ID e2317680121.
Åpne denne publikasjonen i ny fane eller vindu >>A chemical inhibitor of IST1-CHMP1B interaction impairs endosomal recycling and induces noncanonical LC3 lipidation
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2024 (engelsk)Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 121, nr 17, artikkel-id e2317680121Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The endosomal sorting complex required for transport (ESCRT) machinery constitutes multisubunit protein complexes that play an essential role in membrane remodeling and trafficking. ESCRTs regulate a wide array of cellular processes, including cytokinetic abscission, cargo sorting into multivesicular bodies (MVBs), membrane repair, and autophagy. Given the versatile functionality of ESCRTs, and the intricate organizational structure of the ESCRT machinery, the targeted modulation of distinct ESCRT complexes is considerably challenging. This study presents a pseudonatural product targeting IST1-CHMP1B within the ESCRT-III complexes. The compound specifically disrupts the interaction between IST1 and CHMP1B, thereby inhibiting the formation of IST1-CHMP1B copolymers essential for normal-topology membrane scission events. While the compound has no impact on cytokinesis, MVB sorting, or biogenesis of extracellular vesicles, it rapidly inhibits transferrin receptor recycling in cells, resulting in the accumulation of transferrin in stalled sorting endosomes. Stalled endosomes become decorated by lipidated LC3, suggesting a link between noncanonical LC3 lipidation and inhibition of the IST1-CHMP1B complex.

sted, utgiver, år, opplag, sider
Proceedings of the National Academy of Sciences, 2024
Emneord
endosomal recycling, ESCRT, IST1-CHMP1B, noncanonical LC3 lipidation, Tantalosin
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-225949 (URN)10.1073/pnas.2317680121 (DOI)001222975200010 ()38635626 (PubMedID)2-s2.0-85191105662 (Scopus ID)
Forskningsfinansiär
EU, European Research CouncilSwedish Research Council, 2018-04585Swedish Research Council, 2022-02932Swedish Research Council, 2018–05851Swedish Research Council, 2021–01145Knut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and Medicine
Tilgjengelig fra: 2024-06-12 Laget: 2024-06-12 Sist oppdatert: 2024-06-12bibliografisk kontrollert
Corkery, D. P. & Wu, Y.-W. (2024). ATG12–ATG5-TECPR1: an alternative E3-like complex utilized during the cellular response to lysosomal membrane damage. Autophagy, 20(2), 443-444
Åpne denne publikasjonen i ny fane eller vindu >>ATG12–ATG5-TECPR1: an alternative E3-like complex utilized during the cellular response to lysosomal membrane damage
2024 (engelsk)Inngår i: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 20, nr 2, s. 443-444Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

ATG16L1 is an essential component of the Atg8-family protein conjugation machinery, providing membrane targeting for the ATG12–ATG5 conjugate. Recently, we identified an alternative E3-like complex that functions independently of ATG16L1. This complex utilizes the autophagosome-lysosome tethering factor TECPR1 for membrane targeting. TECPR1 is recruited to damaged lysosomal membranes via a direct interaction with sphingomyelin. At the damaged membrane, TECPR1 assembles into an E3-like complex with ATG12–ATG5 to regulate unconventional LC3 lipidation and promote efficient lysosomal repair.

sted, utgiver, år, opplag, sider
Taylor & Francis, 2024
Emneord
ESCRT, lysophagy, lysosome, membrane repair, TECPR1
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-215934 (URN)10.1080/15548627.2023.2267414 (DOI)001095815100001 ()37872727 (PubMedID)2-s2.0-85174580555 (Scopus ID)
Forskningsfinansiär
EU, European Research CouncilGöran Gustafsson Foundation for Research in Natural Sciences and MedicineKnut and Alice Wallenberg FoundationSwedish Research Council, 2018-04585Swedish Research Council, 2022-02932
Tilgjengelig fra: 2023-11-02 Laget: 2023-11-02 Sist oppdatert: 2024-04-26bibliografisk kontrollert
Corkery, D., Castro-Gonzalez, S., Knyazeva, A., Herzog, L. K. & Wu, Y.-W. (2023). An ATG12-ATG5-TECPR1 E3-like complex regulates unconventional LC3 lipidation at damaged lysosomes. EMBO Reports, 24(9), Article ID e56841.
Åpne denne publikasjonen i ny fane eller vindu >>An ATG12-ATG5-TECPR1 E3-like complex regulates unconventional LC3 lipidation at damaged lysosomes
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2023 (engelsk)Inngår i: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 24, nr 9, artikkel-id e56841Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Lysosomal membrane damage represents a threat to cell viability. As such, cells have evolved sophisticated mechanisms to maintain lysosomal integrity. Small membrane lesions are detected and repaired by the endosomal sorting complex required for transport (ESCRT) machinery while more extensively damaged lysosomes are cleared by a galectin-dependent selective macroautophagic pathway (lysophagy). In this study, we identify a novel role for the autophagosome-lysosome tethering factor, TECPR1, in lysosomal membrane repair. Lysosomal damage promotes TECPR1 recruitment to damaged membranes via its N-terminal dysferlin domain. This recruitment occurs upstream of galectin and precedes the induction of lysophagy. At the damaged membrane, TECPR1 forms an alternative E3-like conjugation complex with the ATG12-ATG5 conjugate to regulate ATG16L1-independent unconventional LC3 lipidation. Abolishment of LC3 lipidation via ATG16L1/TECPR1 double knockout impairs lysosomal recovery following damage.

sted, utgiver, år, opplag, sider
EMBO Press, 2023
Emneord
autophagy, lysophagy, lysosome, membrane repair, TECPR1
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-212078 (URN)10.15252/embr.202356841 (DOI)001018486400001 ()37381828 (PubMedID)2-s2.0-85163748819 (Scopus ID)
Forskningsfinansiär
EU, European Research CouncilSwedish Research Council, 2018-04585Swedish Research Council, 2022-02932Knut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and Medicine
Tilgjengelig fra: 2023-07-17 Laget: 2023-07-17 Sist oppdatert: 2024-03-27bibliografisk kontrollert
Corkery, D. P. & Wu, Y.-W. (2023). Eating while intoxicated: characterizing the molecular mechanism behind V. cholerae toxin MakA-regulated autophagy. Autophagy, 19(6), 1885-1886
Åpne denne publikasjonen i ny fane eller vindu >>Eating while intoxicated: characterizing the molecular mechanism behind V. cholerae toxin MakA-regulated autophagy
2023 (engelsk)Inngår i: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 19, nr 6, s. 1885-1886Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Extracellular pathogens utilize secreted virulence factors to regulate host cell function. Recently we characterized the molecular mechanism behind host macroautophagy/autophagy regulation by the Vibrio cholerae toxin MakA. Cholesterol binding at the plasma membrane induces MakA endocytosis and pH-dependent pore assembly. Membrane perforation of late endosomal membranes induces cellular membrane repair pathways and V-ATPase-dependent unconventional LC3 lipidation on damaged membranes.

sted, utgiver, år, opplag, sider
Taylor & Francis, 2023
Emneord
Cholesterol, MakA, non-canonical autophagy, pore-forming toxin, Vibrio cholerae
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-201429 (URN)10.1080/15548627.2022.2146893 (DOI)000889483900001 ()36409136 (PubMedID)2-s2.0-85142433378 (Scopus ID)
Forskningsfinansiär
Swedish Research Council, 2018-04585Knut and Alice Wallenberg FoundationEU, Horizon 2020Göran Gustafsson Foundation for Research in Natural Sciences and Medicine
Tilgjengelig fra: 2022-12-01 Laget: 2022-12-01 Sist oppdatert: 2023-07-12bibliografisk kontrollert
Corkery, D., Ursu, A., Lucas, B., Grigalunas, M., Kriegler, S., Oliva, R., . . . Waldmann, H. (2023). Inducin triggers LC3-lipidation and ESCRT-mediated lysosomal membrane repair. ChemBioChem (Print), 24(24), Article ID e202300579.
Åpne denne publikasjonen i ny fane eller vindu >>Inducin triggers LC3-lipidation and ESCRT-mediated lysosomal membrane repair
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2023 (engelsk)Inngår i: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 24, nr 24, artikkel-id e202300579Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Lipidation of the LC3 protein has frequently been employed as a marker of autophagy. However, LC3-lipidation is also triggered by stimuli not related to canonical autophagy. Therefore, characterization of the driving parameters for LC3 lipidation is crucial to understanding the biological roles of LC3. We identified a pseudo-natural product, termed Inducin, that increases LC3 lipidation independently of canonical autophagy, impairs lysosomal function and rapidly recruits Galectin 3 to lysosomes. Inducin treatment promotes Endosomal Sorting Complex Required for Transport (ESCRT)-dependent membrane repair and transcription factor EB (TFEB)-dependent lysosome biogenesis ultimately leading to cell death.

sted, utgiver, år, opplag, sider
Wiley-VCH Verlagsgesellschaft, 2023
Emneord
biological activity, endolysosomal membrane damage, LC3 lipidation, lysosomal membrane permeabilization, small molecule
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-216651 (URN)10.1002/cbic.202300579 (DOI)001097711600001 ()37869939 (PubMedID)2-s2.0-85175865186 (Scopus ID)
Forskningsfinansiär
Max Planck SocietySwedish Research Council, 2018-04585Swedish Research Council, 2022-02932Knut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineEU, FP7, Seventh Framework Programme, FP7/2007-2013German Research Foundation (DFG), EXC 2033–390677874– RESOLV
Tilgjengelig fra: 2023-11-28 Laget: 2023-11-28 Sist oppdatert: 2024-01-15bibliografisk kontrollert
Niggemeyer, G., Knyazeva, A., Gasper, R., Corkery, D., Bodenbinder, P., Holstein, J. J., . . . Waldmann, H. (2022). Synthesis of 20-Membered Macrocyclic Pseudo-Natural Products Yields Inducers of LC3 Lipidation. Angewandte Chemie International Edition, 61(11), Article ID e202114328.
Åpne denne publikasjonen i ny fane eller vindu >>Synthesis of 20-Membered Macrocyclic Pseudo-Natural Products Yields Inducers of LC3 Lipidation
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2022 (engelsk)Inngår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 61, nr 11, artikkel-id e202114328Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Design and synthesis of pseudo-natural products (PNPs) through recombination of natural product (NP) fragments in unprecedented arrangements enables the discovery of novel biologically relevant chemical matter. With a view to wider coverage of NP-inspired chemical and biological space, we describe the combination of this principle with macrocycle formation. PNP-macrocycles were synthesized efficiently in a stereoselective one-pot procedure including the 1,3-dipolar cycloadditions of different dipolarophiles with dimeric cinchona alkaloid-derived azomethine ylides formed in situ. The 20-membered bis-cycloadducts embody 18 stereocenters and an additional fragment-sized NP-structure. After further functionalization, a collection of 163 macrocyclic PNPs was obtained. Biological investigation revealed potent inducers of the lipidation of the microtubule associated protein 1 light chain 3 (LC3) protein, which plays a prominent role in various autophagy-related processes.

sted, utgiver, år, opplag, sider
Wiley-VCH Verlagsgesellschaft, 2022
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-192165 (URN)10.1002/anie.202114328 (DOI)000746469800001 ()34978373 (PubMedID)2-s2.0-85123464160 (Scopus ID)
Forskningsfinansiär
Swedish Research Council, 2018‐04585Knut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and Medicine
Tilgjengelig fra: 2022-02-04 Laget: 2022-02-04 Sist oppdatert: 2024-03-27bibliografisk kontrollert
Xin, X., Zhang, Y., Gaetani, M., Lundström, S. L., Zubarev, R. A., Zhou, Y., . . . Wu, Y.-W. (2022). Ultrafast and selective labeling of endogenous proteins using affinity-based benzotriazole chemistry. Chemical Science, 13(24), 7240-7246
Åpne denne publikasjonen i ny fane eller vindu >>Ultrafast and selective labeling of endogenous proteins using affinity-based benzotriazole chemistry
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2022 (engelsk)Inngår i: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 13, nr 24, s. 7240-7246Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Chemical modification of proteins is enormously useful for characterizing protein function in complex biological systems and for drug development. Selective labeling of native or endogenous proteins is challenging owing to the existence of distinct functional groups in proteins and in living systems. Chemistry for rapid and selective labeling of proteins remains in high demand. Here we have developed novel affinity labeling probes using benzotriazole (BTA) chemistry. We showed that affinity-based BTA probes selectively and covalently label a lysine residue in the vicinity of the ligand binding site of a target protein with a reaction half-time of 28 s. The reaction rate constant is comparable to the fastest biorthogonal chemistry. This approach was used to selectively label different cytosolic and membrane proteins in vitro and in live cells. BTA chemistry could be widely useful for labeling of native/endogenous proteins, target identification and development of covalent inhibitors.

sted, utgiver, år, opplag, sider
Royal Society of Chemistry, 2022
Emneord
affinity labeling, benzotriazole, inhibitors, ligand-directed chemistry, protein modifications
HSV kategori
Forskningsprogram
biologisk kemi
Identifikatorer
urn:nbn:se:umu:diva-199553 (URN)10.1039/d1sc05974b (DOI)000806432100001 ()35799822 (PubMedID)2-s2.0-85131868228 (Scopus ID)
Forskningsfinansiär
Knut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Research Council, 2018-04585EU, Horizon 2020, ChemBioAPScience for Life Laboratory, SciLifeLab
Tilgjengelig fra: 2022-09-20 Laget: 2022-09-20 Sist oppdatert: 2022-09-20bibliografisk kontrollert
Jia, X., Knyazeva, A., Zhang, Y., Castro-Gonzalez, S., Nakamura, S., Carlson, L.-A., . . . Wu, Y.-W. (2022). V. cholerae MakA is a cholesterol-binding pore-forming toxin that induces non-canonical autophagy. Journal of Cell Biology, 221(12), Article ID e202206040.
Åpne denne publikasjonen i ny fane eller vindu >>V. cholerae MakA is a cholesterol-binding pore-forming toxin that induces non-canonical autophagy
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2022 (engelsk)Inngår i: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 221, nr 12, artikkel-id e202206040Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Pore-forming toxins (PFTs) are important virulence factors produced by many pathogenic bacteria. Here, we show that the Vibrio cholerae toxin MakA is a novel cholesterol-binding PFT that induces non-canonical autophagy in a pH-dependent manner. MakA specifically binds to cholesterol on the membrane at pH < 7. Cholesterol-binding leads to oligomerization of MakA on the membrane and pore formation at pH 5.5. Unlike other cholesterol-dependent cytolysins (CDCs) which bind cholesterol through a conserved cholesterol-binding motif (Thr-Leu pair), MakA contains an Ile-Ile pair that is essential for MakA-cholesterol interaction. Following internalization, endosomal acidification triggers MakA pore-assembly followed by ESCRT-mediated membrane repair and V-ATPase-dependent unconventional LC3 lipidation on the damaged endolysosomal membranes. These findings characterize a new cholesterol-binding toxin that forms pores in a pH-dependent manner and reveals the molecular mechanism of host autophagy manipulation.

sted, utgiver, år, opplag, sider
Rockefeller University Press, 2022
Emneord
cholesterol-binding, MakA, non-canonical autophagy, pore-forming toxin, Vibrio Cholerae
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-200014 (URN)10.1083/jcb.202206040 (DOI)000932911400001 ()36194176 (PubMedID)2-s2.0-85139366240 (Scopus ID)
Forskningsfinansiär
Knut and Alice Wallenberg FoundationEU, European Research CouncilSwedish Research Council, 2018-04585Göran Gustafsson Foundation for Research in Natural Sciences and Medicine
Tilgjengelig fra: 2022-10-05 Laget: 2022-10-05 Sist oppdatert: 2024-03-27bibliografisk kontrollert
Corkery, D., Wu, Y.-W. & Dowaidar, M. (2021). Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy, 17(1), 1-382
Åpne denne publikasjonen i ny fane eller vindu >>Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)
2021 (engelsk)Inngår i: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 17, nr 1, s. 1-382Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

sted, utgiver, år, opplag, sider
Taylor & Francis, 2021
Emneord
Autophagosome, cancer, flux, LC3, lysosome, macroautophagy, neurodegeneration, phagophore, stress, vacuole
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-181919 (URN)10.1080/15548627.2020.1797280 (DOI)000636121800001 ()33634751 (PubMedID)2-s2.0-85102619204 (Scopus ID)
Forskningsfinansiär
NIH (National Institute of Health)
Tilgjengelig fra: 2021-04-01 Laget: 2021-04-01 Sist oppdatert: 2022-10-31bibliografisk kontrollert
Corkery, D., Nadeem, A., Aung, K. M., Hassan, A., Liu, T., Cervantes-Rivera, R., . . . Wu, Y.-W. (2021). Vibrio cholerae cytotoxin MakA induces noncanonical autophagy resulting in the spatial inhibition of canonical autophagy. Journal of Cell Science, 134(5), Article ID jcs252015.
Åpne denne publikasjonen i ny fane eller vindu >>Vibrio cholerae cytotoxin MakA induces noncanonical autophagy resulting in the spatial inhibition of canonical autophagy
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2021 (engelsk)Inngår i: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 134, nr 5, artikkel-id jcs252015Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Autophagy plays an essential role in the defense against manymicrobial pathogens as a regulator of both innate and adaptive immunity. Some pathogens have evolved sophisticated mechanisms that promote their ability to evade or subvert host autophagy. Here, we describe a novel mechanism of autophagy modulation mediated by the recently discovered Vibrio cholerae cytotoxin, motility-associatedkilling factor A (MakA). pH-dependent endocytosis of MakA by host cells resulted in the formation of a cholesterol-rich endolysosomal membrane aggregate in the perinuclear region. Aggregate formation induced the noncanonical autophagy pathway driving unconventional LC3 (herein referring to MAP1LC3B) lipidation on endolysosomal membranes. Subsequent sequestration of the ATG12-ATG5-ATG16L1 E3-like enzyme complex, required for LC3 lipidation at the membranous aggregate, resulted in an inhibition of both canonical autophagy and autophagy-related processes, including the unconventional secretion of interleukin-1β (IL-1β). These findings identify a novel mechanismof host autophagy modulation and immune modulation employed by V. cholerae during bacterial infection.

sted, utgiver, år, opplag, sider
The Company of Biologists, 2021
Emneord
IL-1β, MakA, Bacterial toxin, Membrane aggregate, Noncanonical autophagy, Unconventional secretion
HSV kategori
Identifikatorer
urn:nbn:se:umu:diva-180836 (URN)10.1242/jcs.252015 (DOI)000629619100016 ()33106317 (PubMedID)2-s2.0-85102218537 (Scopus ID)
Forskningsfinansiär
Knut and Alice Wallenberg Foundation, KAW2015.0225The Kempe Foundations, JCK-1528
Tilgjengelig fra: 2021-02-25 Laget: 2021-02-25 Sist oppdatert: 2023-09-05bibliografisk kontrollert
Organisasjoner
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0001-7930-0134