p62/sequestosome-1 associates with and sustains the expression of retroviral restriction factor TRIM5alpha.
TRIM5 proteins mediate a potent block to the cross-species transmission of retroviruses, the most well known being the TRIM5alpha protein from rhesus macaques, which potently inhibits human immunodeficiency virus type 1 (HIV-1) infection. This restriction occurs at an early stage in the replication cycle and is mediated by the binding of TRIM5 proteins to determinants present in the retroviral capsid. TRIM5alpha, as well as other TRIM family proteins, has been shown to be regulated by interferons (IFN). Here we show that TRIM5alpha associates with another IFN-induced gene, sequestosome-1/p62 (p62). p62 plays a role in several signal transduction cascades that are important for maintaining the antiviral state of cells. Here we demonstrate that p62 localizes to both human and rhesus macaque TRIM5alpha cytoplasmic bodies, and fluorescence resonance energy transfer (FRET) analysis demonstrates that these proteins closely associate in these structures. When p62 expression was knocked down via small interfering RNA (siRNA), the number of TRIM5alpha cytoplasmic bodies and the level of TRIM5alpha protein expression were reduced in cell lines stably expressing epitope-tagged versions of TRIM5alpha. In accordance with these data, p62 knockdown resulted in reduced TRIM5alpha-mediated retroviral restriction in cells expressing epitope-tagged TRIM5alpha or expressing endogenously expressed human TRIM5alpha. p62 may therefore operate to enhance TRIM5alpha-mediated retroviral restriction, contributing to the antiviral state of cells following IFN treatment.
O'Connor
Christopher
C
Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois, USA.
Pertel
Thomas
T
Gray
Seth
S
Robia
Seth L
SL
Bakowska
Joanna C
JC
Luban
Jeremy
J
Campbell
Edward M
EM
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D015497:HIV-1; D006801:Humans; D011485:Protein Binding; D012190:Retroviridae / Q000235:genetics / Q000502:physiology*; D012192:Retroviridae Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D000071456:Sequestosome-1 Protein; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D000070584:Tripartite Motif Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases