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Wu, Yao-Wen, ProfessorORCID iD iconorcid.org/0000-0002-2573-8736
Biography [eng]

Our lab is interested in understanding the molecular mechanism of autophagy and membrane trafficking regulated by small GTPases by developing novel chemical and chemo-optogenetic approaches.

Our work lies at the interface between chemistry and biology. On one hand, we develop novel chemical and synthetic approaches that open up new avenue for manipulating protein function and visualizing biological processes in live cells. On the other hand, the application of the diverse tools shed light on the mechanism of autophagy and membrane trafficking, facilitating the development of therapeutics against cancer and neurodegenerative diseases.

Publications (10 of 40) Show all publications
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
Open this publication in new window or tab >>ATG12–ATG5-TECPR1: an alternative E3-like complex utilized during the cellular response to lysosomal membrane damage
2024 (English)In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 20, no 2, p. 443-444Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Taylor & Francis, 2024
Keywords
ESCRT, lysophagy, lysosome, membrane repair, TECPR1
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-215934 (URN)10.1080/15548627.2023.2267414 (DOI)001095815100001 ()37872727 (PubMedID)2-s2.0-85174580555 (Scopus ID)
Funder
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
Available from: 2023-11-02 Created: 2023-11-02 Last updated: 2024-04-26Bibliographically approved
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.
Open this publication in new window or tab >>An ATG12-ATG5-TECPR1 E3-like complex regulates unconventional LC3 lipidation at damaged lysosomes
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2023 (English)In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 24, no 9, article id e56841Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
EMBO Press, 2023
Keywords
autophagy, lysophagy, lysosome, membrane repair, TECPR1
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-212078 (URN)10.15252/embr.202356841 (DOI)001018486400001 ()37381828 (PubMedID)2-s2.0-85163748819 (Scopus ID)
Funder
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
Available from: 2023-07-17 Created: 2023-07-17 Last updated: 2024-03-27Bibliographically approved
Wu, Y.-W. (2023). Controlling cellular activities with light. Nature Methods, 20, 357-358
Open this publication in new window or tab >>Controlling cellular activities with light
2023 (English)In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 20, p. 357-358Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Nature Publishing Group, 2023
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-205803 (URN)10.1038/s41592-022-01745-3 (DOI)000938169100003 ()36823334 (PubMedID)2-s2.0-85149675771 (Scopus ID)
Funder
EU, European Research CouncilSwedish Research Council, 2018-04585Knut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and Medicine
Available from: 2023-03-22 Created: 2023-03-22 Last updated: 2023-09-05Bibliographically approved
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
Open this publication in new window or tab >>Eating while intoxicated: characterizing the molecular mechanism behind V. cholerae toxin MakA-regulated autophagy
2023 (English)In: Autophagy, ISSN 1554-8627, E-ISSN 1554-8635, Vol. 19, no 6, p. 1885-1886Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Taylor & Francis, 2023
Keywords
Cholesterol, MakA, non-canonical autophagy, pore-forming toxin, Vibrio cholerae
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-201429 (URN)10.1080/15548627.2022.2146893 (DOI)000889483900001 ()36409136 (PubMedID)2-s2.0-85142433378 (Scopus ID)
Funder
Swedish Research Council, 2018-04585Knut and Alice Wallenberg FoundationEU, Horizon 2020Göran Gustafsson Foundation for Research in Natural Sciences and Medicine
Available from: 2022-12-01 Created: 2022-12-01 Last updated: 2023-07-12Bibliographically approved
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.
Open this publication in new window or tab >>Inducin triggers LC3-lipidation and ESCRT-mediated lysosomal membrane repair
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2023 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 24, no 24, article id e202300579Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2023
Keywords
biological activity, endolysosomal membrane damage, LC3 lipidation, lysosomal membrane permeabilization, small molecule
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-216651 (URN)10.1002/cbic.202300579 (DOI)001097711600001 ()37869939 (PubMedID)2-s2.0-85175865186 (Scopus ID)
Funder
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
Available from: 2023-11-28 Created: 2023-11-28 Last updated: 2024-01-15Bibliographically approved
Nanda, S., Calderon, A., Sachan, A., Duong, T.-T., Koch, J., Xin, X., . . . Dehmelt, L. (2023). Rho GTPase activity crosstalk mediated by Arhgef11 and Arhgef12 coordinates cell protrusion-retraction cycles. Nature Communications, 14(1), Article ID 8356.
Open this publication in new window or tab >>Rho GTPase activity crosstalk mediated by Arhgef11 and Arhgef12 coordinates cell protrusion-retraction cycles
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2023 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 14, no 1, article id 8356Article in journal (Refereed) Published
Abstract [en]

Rho GTPases play a key role in the spatio-temporal coordination of cytoskeletal dynamics during cell migration. Here, we directly investigate crosstalk between the major Rho GTPases Rho, Rac and Cdc42 by combining rapid activity perturbation with activity measurements in mammalian cells. These studies reveal that Rac stimulates Rho activity. Direct measurement of spatio-temporal activity patterns show that Rac activity is tightly and precisely coupled to local cell protrusions, followed by Rho activation during retraction. Furthermore, we find that the Rho-activating Lbc-type GEFs Arhgef11 and Arhgef12 are enriched at transient cell protrusions and retractions and recruited to the plasma membrane by active Rac. In addition, their depletion reduces activity crosstalk, cell protrusion-retraction dynamics and migration distance and increases migration directionality. Thus, our study shows that Arhgef11 and Arhgef12 facilitate exploratory cell migration by coordinating cell protrusion and retraction by coupling the activity of the associated regulators Rac and Rho.

Place, publisher, year, edition, pages
Springer Nature, 2023
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-218688 (URN)10.1038/s41467-023-43875-y (DOI)38102112 (PubMedID)2-s2.0-85179734469 (Scopus ID)
Funder
German Research Foundation (DFG), 823/3-1, 823/9-1, 823/4-1, 823/6-1, 823/8-1, 823/10-1Knut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and MedicineSwedish Research Council, 2018-04585
Available from: 2023-12-27 Created: 2023-12-27 Last updated: 2023-12-27Bibliographically approved
Kowalczyk, M., Kamps, D., Wu, Y.-W., Dehmelt, L. & Nalbant, P. (2022). Monitoring the Response of Multiple Signal Network Components to Acute Chemo-Optogenetic Perturbations in Living Cellsope. ChemBioChem (Print), 23(4), Article ID e202100582.
Open this publication in new window or tab >>Monitoring the Response of Multiple Signal Network Components to Acute Chemo-Optogenetic Perturbations in Living Cellsope
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2022 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 23, no 4, article id e202100582Article in journal (Refereed) Published
Abstract [en]

Cells process information via signal networks that typically involve multiple components which are interconnected by feedback loops. The combination of acute optogenetic perturbations and microscopy-based fluorescent response readouts enables the direct investigation of causal links in such networks. However, due to overlaps in spectra of photosensitive and fluorescent proteins, current approaches that combine these methods are limited. Here, we present an improved chemo-optogenetic approach that is based on switch-like perturbations induced by a single, local pulse of UV light. We show that this approach can be combined with parallel monitoring of multiple fluorescent readouts to directly uncover relations between signal network components. We present the application of this technique to directly investigate feedback-controlled regulation in the cell contraction signal network that includes GEF-H1, Rho and Myosin, and functional interactions of this network with tumor relevant RhoA G17 mutants.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022
National Category
Cell Biology
Identifiers
urn:nbn:se:umu:diva-191112 (URN)10.1002/cbic.202100582 (DOI)000736123600001 ()34897929 (PubMedID)2-s2.0-85122083067 (Scopus ID)
Available from: 2022-01-10 Created: 2022-01-10 Last updated: 2022-07-14Bibliographically approved
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.
Open this publication in new window or tab >>Synthesis of 20-Membered Macrocyclic Pseudo-Natural Products Yields Inducers of LC3 Lipidation
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2022 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 61, no 11, article id e202114328Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2022
National Category
Organic Chemistry
Identifiers
urn:nbn:se:umu:diva-192165 (URN)10.1002/anie.202114328 (DOI)000746469800001 ()34978373 (PubMedID)2-s2.0-85123464160 (Scopus ID)
Funder
Swedish Research Council, 2018‐04585Knut and Alice Wallenberg FoundationGöran Gustafsson Foundation for Research in Natural Sciences and Medicine
Available from: 2022-02-04 Created: 2022-02-04 Last updated: 2024-03-27Bibliographically approved
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
Open this publication in new window or tab >>Ultrafast and selective labeling of endogenous proteins using affinity-based benzotriazole chemistry
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2022 (English)In: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 13, no 24, p. 7240-7246Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2022
Keywords
affinity labeling, benzotriazole, inhibitors, ligand-directed chemistry, protein modifications
National Category
Biochemistry and Molecular Biology Other Chemistry Topics Organic Chemistry
Research subject
biological chemistry
Identifiers
urn:nbn:se:umu:diva-199553 (URN)10.1039/d1sc05974b (DOI)000806432100001 ()35799822 (PubMedID)2-s2.0-85131868228 (Scopus ID)
Funder
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
Available from: 2022-09-20 Created: 2022-09-20 Last updated: 2022-09-20Bibliographically approved
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.
Open this publication in new window or tab >>V. cholerae MakA is a cholesterol-binding pore-forming toxin that induces non-canonical autophagy
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2022 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 221, no 12, article id e202206040Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
Rockefeller University Press, 2022
Keywords
cholesterol-binding, MakA, non-canonical autophagy, pore-forming toxin, Vibrio Cholerae
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-200014 (URN)10.1083/jcb.202206040 (DOI)000932911400001 ()36194176 (PubMedID)2-s2.0-85139366240 (Scopus ID)
Funder
Knut and Alice Wallenberg FoundationEU, European Research CouncilSwedish Research Council, 2018-04585Göran Gustafsson Foundation for Research in Natural Sciences and Medicine
Available from: 2022-10-05 Created: 2022-10-05 Last updated: 2024-03-27Bibliographically approved
Projects
The role of phosphoinositides in autophagosome formation [2018-04585_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-2573-8736

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