A naturally occurring 22-amino acid fragment of human hemoglobin A inhibits autophagy and HIV-1.

Autor: Freisem D; Institute of Molecular Virology, Ulm University Medical Center, Meyerhofstraße 1, 89081, Ulm, Germany., Rodriguez-Alfonso AA; Core Facility Functional Peptidomics, Ulm University, Meyerhofstraße 4, 89081, Ulm, Germany.; Core Unit Mass Spectrometry and Proteomics, Ulm University Medical Center, Albert-Einstein-Allee 11, 89081, Ulm, Germany., Lawrenz J; Institute of Molecular Virology, Ulm University Medical Center, Meyerhofstraße 1, 89081, Ulm, Germany., Zhou Z; Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany., Monecke T; Institute of Pharmaceutical Biotechnology, Ulm University, James-Franck-Ring N27, 89081, Ulm, Germany., Preising N; Core Facility Functional Peptidomics, Ulm University, Meyerhofstraße 4, 89081, Ulm, Germany., Endres S; Core Unit Mass Spectrometry and Proteomics, Ulm University Medical Center, Albert-Einstein-Allee 11, 89081, Ulm, Germany.; Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center, Albert-Einstein-Allee 11, 89081, Ulm, Germany., Wiese S; Core Unit Mass Spectrometry and Proteomics, Ulm University Medical Center, Albert-Einstein-Allee 11, 89081, Ulm, Germany., Ständker L; Core Facility Functional Peptidomics, Ulm University, Meyerhofstraße 4, 89081, Ulm, Germany., Kuan SL; Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany., Thal DR; Laboratory of Neuropathology, Institute of Pathology, Center for Clinical Research at the University of Ulm, 89081, Ulm, Germany.; Laboratory of Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute, KU Leuven, Louvain, Belgium., Weil T; Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany., Niessing D; Institute of Pharmaceutical Biotechnology, Ulm University, James-Franck-Ring N27, 89081, Ulm, Germany., Barth H; Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center, Albert-Einstein-Allee 11, 89081, Ulm, Germany., Kirchhoff F; Institute of Molecular Virology, Ulm University Medical Center, Meyerhofstraße 1, 89081, Ulm, Germany., Harms M; Institute of Molecular Virology, Ulm University Medical Center, Meyerhofstraße 1, 89081, Ulm, Germany., Münch J; Institute of Molecular Virology, Ulm University Medical Center, Meyerhofstraße 1, 89081, Ulm, Germany., Sparrer KMJ; Institute of Molecular Virology, Ulm University Medical Center, Meyerhofstraße 1, 89081, Ulm, Germany. Konstantin.Sparrer@uni-ulm.de.
Jazyk: angličtina
Zdroj: Cellular and molecular life sciences : CMLS [Cell Mol Life Sci] 2024 Sep 17; Vol. 81 (1), pp. 409. Date of Electronic Publication: 2024 Sep 17.
DOI: 10.1007/s00018-024-05447-1
Abstrakt: Autophagy is an evolutionarily ancient catabolic pathway and has recently emerged as an integral part of the innate immune system. While the core machinery of autophagy is well defined, the physiological regulation of autophagy is less understood. Here, we identify a C-terminal fragment of human hemoglobin A (HBA1, amino acids 111-132) in human bone marrow as a fast-acting non-inflammatory inhibitor of autophagy initiation. It is proteolytically released from full-length HBA1 by cathepsin E, trypsin or pepsin. Biochemical characterization revealed that HBA1(111-132) has an in vitro stability of 52 min in human plasma and adopts a flexible monomeric conformation in solution. Structure-activity relationship studies revealed that the C-terminal 13 amino acids of HBA1(120-132) are sufficient to inhibit autophagy, two charged amino acids (D127, K128) mediate solubility, and two serines (S125, S132) are required for function. Successful viruses like human immunodeficiency virus 1 (HIV-1) evolved strategies to subvert autophagy for virion production. Our results show that HBA1(120-132) reduced virus yields of lab-adapted and primary HIV-1. Summarizing, our data identifies naturally occurring HBA1(111-132) as a physiological, non-inflammatory antagonist of autophagy. Optimized derivatives of HBA1(111-132) may offer perspectives to restrict autophagy-dependent viruses.
(© 2024. The Author(s).)
Databáze: MEDLINE
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