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V. cholerae MakA is a cholesterol-binding pore-forming toxin that induces non-canonical autophagy
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).ORCID-id: 0000-0002-1700-3668
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR).
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2022 (Engelska)Ingår i: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 221, nr 12, artikel-id e202206040Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
Rockefeller University Press, 2022. Vol. 221, nr 12, artikel-id e202206040
Nyckelord [en]
cholesterol-binding, MakA, non-canonical autophagy, pore-forming toxin, Vibrio Cholerae
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:umu:diva-200014DOI: 10.1083/jcb.202206040ISI: 000932911400001PubMedID: 36194176Scopus ID: 2-s2.0-85139366240OAI: oai:DiVA.org:umu-200014DiVA, id: diva2:1701387
Forskningsfinansiär
Knut och Alice Wallenbergs StiftelseEU, Europeiska forskningsrådetVetenskapsrådet, 2018-04585Göran Gustafssons stiftelse för naturvetenskaplig och medicinsk forskning (KVA)Tillgänglig från: 2022-10-05 Skapad: 2022-10-05 Senast uppdaterad: 2024-03-27Bibliografiskt granskad
Ingår i avhandling
1. Non-canonical ATG8 conjugation in ESCRT-driven membrane remodeling processes
Öppna denna publikation i ny flik eller fönster >>Non-canonical ATG8 conjugation in ESCRT-driven membrane remodeling processes
2024 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Alternativ titel[sv]
Okonventionell ATG8-konjugering i ESCRT-drivna membranombyggnadsprocesser
Abstract [en]

ATG8 family proteins have the unique ability to conjugate to membrane lipids. Initially identified as a hallmark of autophagy, ATG8 lipidation is emerging as an important regulator of a growing list of non-degradative cellular functions. In this thesis we developed and applied novel chemical genetic approaches to perturb dynamic membrane remodeling processes and induce non-canonical ATG8 conjugation in cells. We investigated novel roles of ATG8 in membrane deformation processes carried out by the Endosomal Sorting Complex Requiredfor Transport (ESCRT) machinery.

In Paper I, using a high-throughput phenotypic screening assay, we developed a collection of pseudo-natural product-based compounds which potently induce ATG8 lipidation in mammalian cells. The most potent compound, Tantalosin, induces ATG8 lipidation which is insensitive to simultaneous inhibition of autophagosome-lysosome fusion, suggesting a non-canonical function ofTantalosin-induced ATG8 conjugation.

In Paper II we investigated the molecular target of Tantalosin. We found that Tantalosin targets the ESCRT-III protein IST1 and inhibits IST1-CHMP1B copolymer formation. This inhibition results in the impairment of transferrin receptor (TfR) recycling resulting in the rapid accumulation of the receptor inearly/sorting endosomes. At the same time, Tantalosin induces non-canonical ATG8 conjugation on stalled sorting endosomes containing TfR. This conjugation is dependent on the ATG16L1-ATG5-ATG12 complex which is recruited to stalled endosomes via ATG16L1-V-ATPase interaction.

In Paper III and Paper IV we studied the induction of non-canonical ATG8 lipidation in response to endolysosomal membrane damage. We used two established membrane damaging agents: V. Cholerae cytotoxin MakA and the lysosomotropic compound, LLOMe. In Paper III we demonstrated that, at lowpH, MakA assembles into small pores in endosomal membranes which arerecognized by the ESCRT membrane repair machinery. Non-canonical ATG8 lipidation in response to MakA-induced pore formation is mediated by V-ATPase activity. In Paper IV we identified a novel player in the lysosomal damage response – TECRP1. TECPR1 is recruited to damaged membranes where it forms an alternative ATG16L1-independent E3 ligase complex with the ATG5-ATG12 conjugate and plays a role in the restoration of lysosomal integrity after damage.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2024. s. 70
Nyckelord
ATG8 conjugation, Endosomal Sorting Complex Required for Transport, membrane remodeling, chemical genetics
Nationell ämneskategori
Cellbiologi Biokemi och molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-222756 (URN)978-91-8070-356-7 (ISBN)978-91-8070-357-4 (ISBN)
Disputation
2024-04-26, Stora Hörsalen, KBC byggnad KBE303, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2024-04-05 Skapad: 2024-03-27 Senast uppdaterad: 2024-03-27Bibliografiskt granskad

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Jia, XiaotongKnyazeva, AnastasiaZhang, YuCastro-Gonzalez, SergioCarlson, Lars-AndersCorkery, DaleWu, Yao-Wen

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Jia, XiaotongKnyazeva, AnastasiaZhang, YuCastro-Gonzalez, SergioCarlson, Lars-AndersYoshimori, TamotsuCorkery, DaleWu, Yao-Wen
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Kemiska institutionenUmeå Centre for Microbial Research (UCMR)Institutionen för medicinsk kemi och biofysikMolekylär Infektionsmedicin, Sverige (MIMS)Wallenberg centrum för molekylär medicin vid Umeå universitet (WCMM)
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Journal of Cell Biology
Biokemi och molekylärbiologi

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