Identification of human T cell leukemia virus type 1 tax amino acid signals and cellular factors involved in secretion of the viral oncoprotein.
Human T cell leukemia virus type 1 (HTLV-1) is the etiologic agent of a number of pathologic abnormalities, including adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The viral oncoprotein Tax has been implicated in the pathogenesis of these diseases. Recently, cell-free Tax was detected in the cerebrospinal fluid of HAM/TSP patients, implying that extracellular Tax may be relevant to neurologic disease. Additionally, the presence of a nuclear export signal within Tax and its active secretion has been demonstrated in vitro. However, the mechanism of Tax secretion remains to be established. Studies reported herein elucidate the process of Tax secretion and identify domains of Tax critical to its subcellular localization and secretion. Tax was shown to interact with a number of cellular secretory pathway proteins in both the model cell line BHK (baby hamster kidney)-21 and an HTLV-1-infected T cell line, C8166, physiologically relevant to HTLV-1-induced disease. Silencing of selected components of the secretory pathway affected Tax secretion, further confirming regulated secretion of Tax. Additionally, mutations in two putative secretory signals within Tax DHE and YTNI resulted in aberrant subcellular localization of Tax and significantly altered protein secretion. Together, these studies demonstrate that Tax secretion is a regulated event facilitated by its interactions with proteins of the cellular secretory pathway and the presence of secretory signals within the carboxyl-terminal domain of the protein.
Jain
Pooja
P
Department of Microbiology and Immunology, Center for Molecular Virology and Neuroimmunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA.
Mostoller
Kate
K
Flaig
Katherine E
KE
Ahuja
Jaya
J
Lepoutre
Veronique
V
Alefantis
Timothy
T
Khan
Zafar K
ZK
Wigdahl
Brian
B
D000818:Animals; D006224:Cricetinae; D016356:Gene Products, tax / Q000134:cerebrospinal fluid / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D015368:Human T-lymphotropic virus 1 / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D019169:Jurkat Cells; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000134:cerebrospinal fluid / Q000235:genetics / Q000821:virology; D049790:Nuclear Export Signals / Q000502:physiology*; D015493:Paraparesis, Tropical Spastic / Q000134:cerebrospinal fluid / Q000235:genetics / Q000821:virology; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology
D016356:Gene Products, tax; D049790:Nuclear Export Signals