Biomaterial Database

Lentiviral Nef proteins utilize PAK2-mediated deregulation of cofilin as a general strategy to interfere with actin remodeling. 2010

Bettina Stolp, and Libin Abraham, and Jochen M Rudolph, and Oliver T Fackler

Department of Infectious Diseases, Virology, University of Heidelberg, INF 324, 69120 Heidelberg, Germany. oliver.fackler@med.uni-heidelberg.de

Nef is an accessory protein and pathogenicity factor of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) which elevates virus replication in vivo. We recently described for HIV type 1(SF2) (HIV-1(SF2)) the potent interference of Nef with T-lymphocyte chemotaxis via its association with the cellular kinase PAK2. Mechanistic analysis revealed that this interaction results in deregulation of the actin-severing factor cofilin and thus blocks the chemokine-mediated actin remodeling required for cell motility. However, the efficiency of PAK2 association is highly variable among Nef proteins from different lentiviruses, prompting us to evaluate the conservation of this actin-remodeling/cofilin-deregulating mechanism. Based on the analysis of a total of 17 HIV-1, HIV-2, and SIV Nef proteins, we report here that inhibition of chemokine-induced actin remodeling as well as inactivation of cofilin are strongly conserved activities of lentiviral Nef proteins. Of note, even for Nef variants that display only marginal PAK2 association in vitro, these activities require the integrity of a PAK2 recruitment motif and the presence of endogenous PAK2. Thus, reduced in vitro affinity to PAK2 does not indicate limited functionality of Nef-PAK2 complexes in intact HIV-1 host cells. These results establish hijacking of PAK2 for deregulation of cofilin and inhibition of triggered actin remodeling as a highly conserved function of lentiviral Nef proteins, supporting the notion that PAK2 association may be critical for Nef's activity in vivo.

UI	MeSH Term	Description	Entries
D011485	Protein Binding	The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.	Plasma Protein Binding Capacity,Binding, Protein
D002460	Cell Line	Established cell cultures that have the potential to propagate indefinitely.	Cell Lines,Line, Cell,Lines, Cell
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000199	Actins	Filamentous proteins that are the main constituent of the thin filaments of muscle fibers. The filaments (known also as filamentous or F-actin) can be dissociated into their globular subunits; each subunit is composed of a single polypeptide 375 amino acids long. This is known as globular or G-actin. In conjunction with MYOSINS, actin is responsible for the contraction and relaxation of muscle.	F-Actin,G-Actin,Actin,Isoactin,N-Actin,alpha-Actin,alpha-Isoactin,beta-Actin,gamma-Actin,F Actin,G Actin,N Actin,alpha Actin,alpha Isoactin,beta Actin,gamma Actin
D015302	Simian Immunodeficiency Virus	Species of the genus LENTIVIRUS, subgenus primate immunodeficiency viruses (IMMUNODEFICIENCY VIRUSES, PRIMATE), that induces acquired immunodeficiency syndrome in monkeys and apes (SAIDS). The genetic organization of SIV is virtually identical to HIV.	SIV (Simian immunodeficiency virus),Immunodeficiency Viruses, Simian,Simian Immunodeficiency Viruses,Immunodeficiency Virus, Simian
D015497	HIV-1	The type species of LENTIVIRUS and the etiologic agent of AIDS. It is characterized by its cytopathic effect and affinity for the T4-lymphocyte.	Human immunodeficiency virus 1,HIV-I,Human Immunodeficiency Virus Type 1,Immunodeficiency Virus Type 1, Human
D015498	HIV-2	An HIV species related to HIV-1 but carrying different antigenic components and with differing nucleic acid composition. It shares serologic reactivity and sequence homology with the simian Lentivirus SIMIAN IMMUNODEFICIENCY VIRUS and infects only T4-lymphocytes expressing the CD4 phenotypic marker.	HTLV-IV,Human T-Lymphotropic Virus Type IV,Human immunodeficiency virus 2,LAV-2,HIV-II,Human Immunodeficiency Virus Type 2,Human T Lymphotropic Virus Type IV,Immunodeficiency Virus Type 2, Human,SBL-6669
D051339	Actin Depolymerizing Factors	A family of low MOLECULAR WEIGHT actin-binding proteins found throughout eukaryotes. They remodel the actin CYTOSKELETON by severing ACTIN FILAMENTS and increasing the rate of monomer dissociation.	Actin Depolymerizing Protein,Cofilin,Cofilins,ADF Proteins (Actin Depolymerizing Factors),Actin Depolymerizing Proteins,Cofilin Proteins,Depolymerizing Factors, Actin,Depolymerizing Protein, Actin,Depolymerizing Proteins, Actin,Protein, Actin Depolymerizing
D054311	nef Gene Products, Human Immunodeficiency Virus	Proteins encoded by the NEF GENES of the HUMAN IMMUNODEFICIENCY VIRUS.	nef Protein, Human Immunodeficiency Virus,HIV-3'-orf Protein,nef Protein, HIV,HIV 3' orf Protein,HIV nef Protein
D054334	Viral Regulatory and Accessory Proteins	A broad category of viral proteins that play indirect roles in the biological processes and activities of viruses. Included here are proteins that either regulate the expression of viral genes or are involved in modifying host cell functions. Many of the proteins in this category serve multiple functions.	Viral Accessory Proteins,Viral Regulatory Proteins,Regulatory Proteins, Viral,Accessory Proteins, Viral,Proteins, Viral Accessory,Proteins, Viral Regulatory