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P62/sequestosome-1 associates with and sustains the expression of retroviral restriction factor TRIM5alpha.

ABSTRACT: 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.

SUBMITTER: O'Connor C

PROVIDER: S-EPMC2876647 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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p62/sequestosome-1 associates with and sustains the expression of retroviral restriction factor TRIM5alpha.

O'Connor Christopher C Pertel Thomas T Gray Seth S Robia Seth L SL Bakowska Joanna C JC Luban Jeremy J Campbell Edward M EM

Journal of virology 20100331 12

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 interferon ...[more]

PMID: 20357094

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Project description:Diffuse myofiber necrosis in the context of inflammatory myopathy is the hallmark of immune-mediated necrotizing myopathy (IMNM). We have previously shown that skeletal muscle fibers of IMNM patients may display nonrimmed vacuoles and sarcoplasmic irregularities. The dysfunctional chaperone activity has been linked to the defective assembly of skeletal muscle proteins and their degradation via lysosomes, autophagy and the proteasomal machinery. This study was undertaken to highlight a chaperone-assisted selective autophagy (CASA) pathway, functionally involved in protein homeostasis, cell stress and the immune response in skeletal muscle of IMNM patients. Skeletal muscle biopsies from 54 IMNM patients were analyzed by immunostaining, as well as by qPCR. Eight biopsies of sIBM patients served as pathological controls, and eight biopsies of nondisease control subjects were included. Alteration of autophagy was detectable in all IMNM biopsy samples highlighted via a diffuse sarcoplasmic staining pattern by p62 and LC3 independent of vacuoles. This pattern was at variance with the coarse focal staining pattern mostly confined to rimmed vacuoles in sIBM. Colocalization of p62 with the chaperone proteins HSP70 and αB-crystalline points to the specific targeting of misfolded proteins to the CASA machinery. Bcl2-associated athanogene 3 (BAG3) positivity of these fibers emphasizes the selectivity of autophagy processes and these fibers also express MHC class I sarcolemma. Expression of genes involved in autophagy and endoplasmic reticulum (ER) stress pathways studied here is significantly upregulated in IMNM. We highlight that vacuoles without sarcolemmal features may arise in IMNM muscle biopsies, and they must not be confounded with sIBM-specific vacuoles. Further, we show the activation of selective autophagy and emphasize the role of chaperones in this context. CASA occurs in IMNM muscle, and specific molecular pathways of autophagy differ from the ones in sIBM, with p62 as a unique identifier of this process.

Dataset Information

P62/sequestosome-1 associates with and sustains the expression of retroviral restriction factor TRIM5alpha.

Publications

p62/sequestosome-1 associates with and sustains the expression of retroviral restriction factor TRIM5alpha.

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