title: Cellular aspartyl proteases promote the unconventional secretion of biologically active HIV-1 matrix protein p17.
abstract: The human immune deficiency virus type 1 (HIV-1) matrix protein p17 (p17), although devoid of a signal sequence, is released by infected cells and detected in blood and in different organs and tissues even in HIV-1-infected patients undergoing successful combined antiretroviral therapy (cART). Extracellularly, p17 deregulates the function of different cells involved in AIDS pathogenesis. The mechanism of p17 secretion, particularly during HIV-1 latency, still remains to be elucidated. A recent study showed that HIV-1-infected cells can produce Gag without spreading infection in a model of viral latency. Here we show that in Gag-expressing cells, secretion of biologically active p17 takes place at the plasma membrane and occurs following its interaction with phosphatidylinositol-(4,5)-bisphosphate and its subsequent cleavage from the precursor Gag (Pr55Gag) operated by cellular aspartyl proteases. These enzymes operate a more complex Gag polypeptide proteolysis than the HIV-1 protease, thus hypothetically generating slightly truncated or elongated p17s in their C-terminus. A 17 C-terminal residues excised p17 was found to be structurally and functionally identical to the full-length p17 demonstrating that the final C-terminal region of p17 is irrelevant for the protein's biological activity. These findings offer new opportunities to identify treatment strategies for inhibiting p17 release in the extracellular microenvironment.
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Caccuri
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Iaria
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Campilongo
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Varney
authors.affiliation: IRCCS Istituto di Ricerche Farmacologiche "Mario Negri" Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Mitola
authors.affiliation: IRCCS Istituto di Ricerche Farmacologiche "Mario Negri" Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schiarea
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Bugatti
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Mazzuca
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giagulli
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Fiorentini
authors.affiliation: Institute of Human Virology, University of Maryland, Baltimore, Maryland, USA.
authors.forename: Wuyuan
authors.initials: W
authors.lastname: Lu
authors.affiliation: IRCCS Istituto di Ricerche Farmacologiche "Mario Negri" Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia Medical School, Brescia, Italy.
authors.forename: Arnaldo
authors.initials: A
authors.lastname: Caruso
mesh_terms: D057055:Aspartic Acid Proteases / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D015488:HIV Antigens / Q000737:chemistry; D015658:HIV Infections / Q000378:metabolism / Q000821:virology*; D015497:HIV-1 / Q000378:metabolism / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D017735:Virus Latency; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000378:metabolism*
chemical_list: D015488:HIV Antigens; D019269:Phosphatidylinositol 4,5-Diphosphate; D011498:Protein Precursors; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1; C059767:p55 gag precursor protein, Human immunodeficiency virus 1; D057055:Aspartic Acid Proteases