Skip to main content

Advertisement

SpringerLink
Log in

Neuronal PINCH is Regulated by TNF-α and is Required for Neurite Extension

  • ORIGINAL ARTICLE
  • Published:
Journal of Neuroimmune Pharmacology Aims and scope Submit manuscript

Abstract

During HIV infection of the CNS, neurons are damaged by viral proteins, such as Tat and gp120, or by inflammatory factors, such as TNF-α, that are released from infected and/or activated glial cells. Host responses to this damage may include the induction of survival or repair mechanisms. In this context, previous studies report robust expression of a protein called particularly interesting new cysteine histidine-rich protein (PINCH), in the neurons of HIV patients’ brains, compared with nearly undetectable levels in HIV-negative individuals (Rearden et al., J Neurosci Res 86:2535–2542, 2008), suggesting PINCH’s involvement in neuronal signaling during HIV infection of the brain. To address potential triggers for PINCH induction in HIV patients’ brains, an in vitro system mimicking some aspects of HIV infection of the CNS was utilized. We investigated neuronal PINCH expression, subcellular distribution, and biological consequences of PINCH sequestration upon challenge with Tat, gp120, and TNF-α. Our results indicate that in neurons, TNF-α stimulation increases PINCH expression and changes its subcellular localization. Furthermore, PINCH mobility is required to maintain neurite extension upon challenge with TNF-α. PINCH may function as a neuron-specific host-mediated response to challenge by HIV-related factors in the CNS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Acconcia F, Barnes CJ, Singh RR, Talukder AH, Kumar R (2007) Phosphorylation-dependent regulation of nuclear localization and functions of integrin-linked kinase. Proc Natl Acad Sci USA 104:6782–6787

    Article  PubMed  CAS  Google Scholar 

  • Achim CL, Heyes MP, Wiley CA (1993) Quantitation of human immunodeficiency virus, immune activation factors, and quinolinic acid in AIDS brains. J Clin Invest 91:2769–2775

    Article  PubMed  CAS  Google Scholar 

  • Adle-Biassette H, Chretien F, Wingertsmann L, Hery C, Ereau T, Scaravilli F, Tardieu M, Gray F (1999) Neuronal apoptosis does not correlate with dementia in HIV infection but is related to microglial activation and axonal damage. Neuropathol Appl Neurobiol 25:123–133

    Article  PubMed  CAS  Google Scholar 

  • Aukrust P, Liabakk NB, Muller F, Lien E, Espevik T, Froland SS (1994) Serum levels of tumor necrosis factor-alpha (TNF alpha) and soluble TNF receptors in human immunodeficiency virus type 1 infection—correlations to clinical, immunologic, and virologic parameters. J Infect Dis 169:420–424

    Article  PubMed  CAS  Google Scholar 

  • Bansal AK, Mactutus CF, Nath A, Maragos W, Hauser KF, Booze RM (2000) Neurotoxicity of HIV-1 proteins gp120 and Tat in the rat striatum. Brain Res 879:42–49

    Article  PubMed  CAS  Google Scholar 

  • Bezzi P, Domercq M, Brambilla L, Galli R, Schols D, De Clercq E, Vescovi A, Bagetta G, Kollias G, Meldolesi J, Volterra A (2001) CXCR4-activated astrocyte glutamate release via TNFalpha: amplification by microglia triggers neurotoxicity. Nat Neurosci 4:702–710

    Article  PubMed  CAS  Google Scholar 

  • Buonaguro L, Barillari G, Chang HK, Bohan CA, Kao V, Morgan R, Gallo RC, Ensoli B (1992) Effects of the human immunodeficiency virus type 1 Tat protein on the expression of inflammatory cytokines. J Virol 66:7159–7167

    PubMed  CAS  Google Scholar 

  • Buriani A, Petrelli L, Facci L, Romano PG, Dal Tosso R, Leon A, Skaper SD (1999) Human immunodeficiency virus type 1 envelope glycoprotein gp120 induces tumor necrosis factor-alpha in astrocytes. J NeuroAIDS 2:1–13

    PubMed  CAS  Google Scholar 

  • Buscemi L, Ramonet D, Geiger JD (2007) Human immunodeficiency virus type-1 protein Tat induces tumor necrosis factor-alpha-mediated neurotoxicity. Neurobiol Dis 26:661–670

    Article  PubMed  CAS  Google Scholar 

  • Campana WM, Myers RR, Rearden A (2003) Identification of PINCH in Schwann cells and DRG neurons: shuttling and signaling after nerve injury. Glia 41:213–223

    Article  PubMed  Google Scholar 

  • Chao CC, Hu S (1994) Tumor necrosis factor-alpha potentiates glutamate neurotoxicity in human fetal brain cell cultures. Dev Neurosci 16:172–179

    Article  PubMed  CAS  Google Scholar 

  • Chen K, Tu Y, Zhang Y, Blair HC, Zhang L, Wu C (2008) PINCH-1 regulates the ERK-Bim pathway and contributes to apoptosis resistance in cancer cells. J Biol Chem 283:2508–2517

    Article  PubMed  CAS  Google Scholar 

  • Cherner M, Cysique L, Heaton RK, Marcotte TD, Ellis RJ, Masliah E, Grant I (2007) Neuropathologic confirmation of definitional criteria for human immunodeficiency virus-associated neurocognitive disorders. J Neurovirol 13:23–28

    Article  PubMed  Google Scholar 

  • Chun TW, Engel D, Mizell SB, Ehler LA, Fauci AS (1998) Induction of HIV-1 replication in latently infected CD4+ T cells using a combination of cytokines. J Exp Med 188:83–91

    Article  PubMed  CAS  Google Scholar 

  • Contreras X, Bennasser Y, Chazal N, Moreau M, Leclerc C, Tkaczuk J, Bahraoui E (2005) Human immunodeficiency virus type 1 Tat protein induces an intracellular calcium increase in human monocytes that requires DHP receptors: involvement in TNF-alpha production. Virology 332:316–328

    Article  PubMed  Google Scholar 

  • Del Valle L, Pina-Oviedo S (2006) HIV disorders of the brain: pathology and pathogenesis. Front Biosci 11:718–732

    Article  PubMed  Google Scholar 

  • Dougherty GW, Chopp T, Qi SM, Cutler ML (2005) The Ras suppressor Rsu-1 binds to the LIM 5 domain of the adaptor protein PINCH1 and participates in adhesion-related functions. Exp Cell Res 306:168–179

    Article  PubMed  CAS  Google Scholar 

  • Ellis R, Langford D, Masliah E (2007) HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 8:33–44

    Article  PubMed  CAS  Google Scholar 

  • Fine SM, Angel RA, Perry SW, Epstein LG, Rothstein JD, Dewhurst S, Gelbard HA (1996) Tumor necrosis factor alpha inhibits glutamate uptake by primary human astrocytes. Implications for pathogenesis of HIV-1 dementia. J Biol Chem 271:15303–15306

    Article  PubMed  CAS  Google Scholar 

  • Gelbard HA, Dzenko KA, DiLoreto D, del Cerro C, del Cerro M, Epstein LG (1993) Neurotoxic effects of tumor necrosis factor alpha in primary human neuronal cultures are mediated by activation of the glutamate AMPA receptor subtype: implications for AIDS neuropathogenesis. Dev Neurosci 15:417–422

    Article  PubMed  CAS  Google Scholar 

  • Glass JD, Fedor H, Wesselingh SL, McArthur JC (1995) Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia. Ann Neurol 38:755–762

    Article  PubMed  CAS  Google Scholar 

  • Glowa JR, Panlilio LV, Brenneman DE, Gozes I, Fridkin M, Hill JM (1992) Learning impairment following intracerebral administration of the HIV envelope protein gp120 or a VIP antagonist. Brain Res 570:49–53

    Article  PubMed  CAS  Google Scholar 

  • Grigorian A, Hurford R, Chao Y, Patrick C, Langford TD (2008) Alterations in the Notch4 pathway in cerebral endothelial cells by the HIV aspartyl protease inhibitor, nelfinavir. BMC Neurosci 9:27

    Article  PubMed  Google Scholar 

  • Grimaldi LM, Martino GV, Franciotta DM, Brustia R, Castagna A, Pristera R, Lazzarin A (1991) Elevated alpha-tumor necrosis factor levels in spinal fluid from HIV-1-infected patients with central nervous system involvement. Ann Neurol 29:21–25

    Article  PubMed  CAS  Google Scholar 

  • Guo W, Jiang H, Gray V, Dedhar S, Rao Y (2007) Role of the integrin-linked kinase (ILK) in determining neuronal polarity. Dev Biol 306:457–468

    Article  PubMed  CAS  Google Scholar 

  • Hsiao KC, Brissette RE, Wang P, Fletcher PW, Rodriguez V, Lennick M, Blume AJ, Goldstein NI (2003) Peptides identify multiple hotspots within the ligand binding domain of the TNF receptor 2. Proteome Sci 1:1

    Article  PubMed  Google Scholar 

  • Janabi N, Di Stefano M, Wallon C, Hery C, Chiodi F, Tardieu M (1998) Induction of human immunodeficiency virus type 1 replication in human glial cells after proinflammatory cytokines stimulation: effect of IFNgamma, IL1beta, and TNFalpha on differentiation and chemokine production in glial cells. Glia 23:304–315

    Article  PubMed  CAS  Google Scholar 

  • Jiang Y, Mizisin AP, Rearden A, Jolivalt CG (2010) Diabetes induces changes in ILK, PINCH and components of related pathways in the spinal cord of rats. Brain Res 1332:100–109

    Article  PubMed  CAS  Google Scholar 

  • Kim HJ, Martemyanov KA, Thayer SA (2008) Human immunodeficiency virus protein Tat induces synapse loss via a reversible process that is distinct from cell death. J Neurosci 28:12604–12613

    Article  PubMed  CAS  Google Scholar 

  • Langford D, Sanders VJ, Mallory M, Kaul M, Masliah E (2002) Expression of stromal cell-derived factor 1alpha protein in HIV encephalitis. J Neuroimmunol 127:115–126

    Article  PubMed  CAS  Google Scholar 

  • Langford D, Grigorian A, Hurford R, Adame A, Crews L, Masliah E (2004a) The role of mitochondrial alterations in the combined toxic effects of human immunodeficiency virus Tat protein and methamphetamine on calbindin positive-neurons. J Neurovirol 10:327–337

    Article  PubMed  CAS  Google Scholar 

  • Langford D, Grigorian A, Hurford R, Adame A, Ellis RJ, Hansen L, Masliah E (2004b) Altered P-glycoprotein expression in AIDS patients with HIV encephalitis. J Neuropathol Exp Neurol 63:1038–1047

    PubMed  CAS  Google Scholar 

  • Li F, Zhang Y, Wu C (1999) Integrin-linked kinase is localized to cell–matrix focal adhesions but not cell-cell adhesion sites and the focal adhesion localization of integrin-linked kinase is regulated by the PINCH-binding ANK repeats. J Cell Sci 112(Pt 24):4589–4599

    PubMed  CAS  Google Scholar 

  • Li S, Bordoy R, Stanchi F, Moser M, Braun A, Kudlacek O, Wewer UM, Yurchenco PD, Fassler R (2005) PINCH1 regulates cell–matrix and cell-cell adhesions, cell polarity and cell survival during the peri-implantation stage. J Cell Sci 118:2913–2921

    Article  PubMed  CAS  Google Scholar 

  • Lipton SA (1993) Human immunodeficiency virus-infected macrophages, gp120, and N-methyl-D-aspartate receptor-mediated neurotoxicity. Ann Neurol 33:227–228

    Article  PubMed  CAS  Google Scholar 

  • Magnuson DS, Knudsen BE, Geiger JD, Brownstone RM, Nath A (1995) Human immunodeficiency virus type 1 Tat activates non-N-methyl-D-aspartate excitatory amino acid receptors and causes neurotoxicity. Ann Neurol 37:373–380

    Article  PubMed  CAS  Google Scholar 

  • Merrill JE, Chen IS (1991) HIV-1, macrophages, glial cells, and cytokines in AIDS nervous system disease. FASEB J 5:2391–2397

    PubMed  CAS  Google Scholar 

  • Morris MC, Depollier J, Mery J, Heitz F, Divita G (2001) A peptide carrier for the delivery of biologically active proteins into mammalian cells. Nat Biotechnol 19:1173–1176

    Article  PubMed  CAS  Google Scholar 

  • Nath A (2002) Human immunodeficiency virus (HIV) proteins in neuropathogenesis of HIV dementia. J Infect Dis 186(Suppl 2):S193–S198

    Article  PubMed  CAS  Google Scholar 

  • Nottet HS, Gendelman HE (1995) Unraveling the neuroimmune mechanisms for the HIV-1-associated cognitive/motor complex. Immunol Today 16:441–448

    Article  PubMed  CAS  Google Scholar 

  • Rasband WS (1997) ImageJ. In, 1.37 edition. NIH, Bethesda

  • Rearden A (1994) A new LIM protein containing an autoepitope homologous to “senescent cell antigen”. Biochem Biophys Res Commun 201:1124–1131

    Article  PubMed  CAS  Google Scholar 

  • Rearden A, Hurford RG, Luu N, Kieu E, Sandoval M, Perez-Liz G, Del Valle L, Powell H, Langford TD (2008) Novel expression of PINCH in the CNS and its potential as a biomarker for HIV-associated neurodegeneration. J Neurosci Res 86:2535–2542

    Article  PubMed  CAS  Google Scholar 

  • Remacle AG, Rozanov DV, Baciu PC, Chekanov AV, Golubkov VS, Strongin AY (2005) The transmembrane domain is essential for the microtubular trafficking of membrane type-1 matrix metalloproteinase (MT1-MMP). J Cell Sci 118:4975–4984

    Article  PubMed  CAS  Google Scholar 

  • Rostasy K, Monti L, Yiannoutsos C, Kneissl M, Bell J, Kemper TL, Hedreen JC, Navia BA (1999) Human immunodeficiency virus infection, inducible nitric oxide synthase expression, and microglial activation: pathogenetic relationship to the acquired immunodeficiency syndrome dementia complex. Ann Neurol 46:207–216

    Article  PubMed  CAS  Google Scholar 

  • Sabatier JM, Vives E, Mabrouk K, Benjouad A, Rochat H, Duval A, Hue B, Bahraoui E (1991) Evidence for neurotoxic activity of tat from human immunodeficiency virus type 1. J Virol 65:961–967

    PubMed  CAS  Google Scholar 

  • Saha RN, Pahan K (2003) Tumor necrosis factor-alpha at the crossroads of neuronal life and death during HIV-associated dementia. J Neurochem 86:1057–1071

    Article  PubMed  CAS  Google Scholar 

  • Sevigny JJ, Albert SM, McDermott MP, Schifitto G, McArthur JC, Sacktor N, Conant K, Selnes OA, Stern Y, McClernon DR, Palumbo D, Kieburtz K, Riggs G, Cohen B, Marder K, Epstein LG (2007) An evaluation of neurocognitive status and markers of immune activation as predictors of time to death in advanced HIV infection. Arch Neurol 64:97–102

    Article  PubMed  Google Scholar 

  • Theodore S, Cass WA, Nath A, Steiner J, Young K, Maragos WF (2006) Inhibition of tumor necrosis factor-alpha signaling prevents human immunodeficiency virus-1 protein Tat and methamphetamine interaction. Neurobiol Dis 23:663–668

    Article  PubMed  CAS  Google Scholar 

  • Tu Y, Li F, Wu C (1998) Nck-2, a novel Src homology2/3-containing adaptor protein that interacts with the LIM-only protein PINCH and components of growth factor receptor kinase-signaling pathways. Mol Biol Cell 9:3367–3382

    PubMed  CAS  Google Scholar 

  • Tu Y, Li F, Goicoechea S, Wu C (1999) The LIM-only protein PINCH directly interacts with integrin-linked kinase and is recruited to integrin-rich sites in spreading cells. Mol Cell Biol 19:2425–2434

    PubMed  CAS  Google Scholar 

  • Wesselingh SL, Takahashi K, Glass JD, McArthur JC, Griffin JW, Griffin DE (1997) Cellular localization of tumor necrosis factor mRNA in neurological tissue from HIV-infected patients by combined reverse transcriptase/polymerase chain reaction in situ hybridization and immunohistochemistry. J Neuroimmunol 74:1–8

    Article  PubMed  CAS  Google Scholar 

  • Wesselingh SL, Power C, Glass JD, Tyor WR, McArthur JC, Farber JM, Griffin JW, Griffin DE (1993) Intracerebral cytokine messenger RNA expression in acquired immunodeficiency syndrome dementia. Ann Neurol 33:576–582

    Article  PubMed  CAS  Google Scholar 

  • Wu C (1999) Integrin-linked kinase and PINCH: partners in regulation of cell–extracellular matrix interaction and signal transduction. J Cell Sci 112(Pt 24):4485–4489

    PubMed  CAS  Google Scholar 

  • Wu C (2004) The PINCH–ILK–parvin complexes: assembly, functions and regulation. Biochim Biophys Acta 1692:55–62

    Article  PubMed  CAS  Google Scholar 

  • Yang Y, Guo L, Blattner SM, Mundel P, Kretzler M, Wu C (2005) Formation and phosphorylation of the PINCH-1-integrin linked kinase-alpha-parvin complex are important for regulation of renal glomerular podocyte adhesion, architecture, and survival. J Am Soc Nephrol 16:1966–1976

    Article  PubMed  CAS  Google Scholar 

  • Yao H, Allen JE, Zhu X, Callen S, Buch S (2009) Cocaine and human immunodeficiency virus type 1 gp120 mediate neurotoxicity through overlapping signaling pathways. J Neurovirol 15:164–175

    Article  PubMed  CAS  Google Scholar 

  • Zhang Q, Nottke A, Goodman RH (2005) Homeodomain-interacting protein kinase-2 mediates CtBP phosphorylation and degradation in UV-triggered apoptosis. Proc Natl Acad Sci USA 102:2802–2807

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was made possible by R01MH085602 to TDL. We acknowledge Dr. Ann Rearden for consultation and the HIV Neurobehavioral Research Center (HNRC) and the California NeuroAIDS Tissue Network (CNTN) for providing human brain tissues. The HNRC is supported by center award MH62512 and CNTN by MH059745. We thank Britt Tracy for assistance with manuscript preparation and editing.

Author information

Authors and Affiliations

  1. Department of Neuroscience, Temple University School of Medicine, 3500 N. Broad St., MERB 750, Philadelphia, PA, USA

    Asavari Jatiani, Paola Pannizzo & Dianne Langford

  2. Department of Oncology, Biology and Genetics, University of Genoa, Genoa, Italy

    Elisa Gualco

  3. Department of Pathology, Louisiana State University, New Orleans, LA, USA

    Luis Del-Valle

Authors
  1. Asavari Jatiani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paola Pannizzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elisa Gualco
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Luis Del-Valle
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dianne Langford
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dianne Langford.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jatiani, A., Pannizzo, P., Gualco, E. et al. Neuronal PINCH is Regulated by TNF-α and is Required for Neurite Extension. J Neuroimmune Pharmacol 6, 330–340 (2011). https://doi.org/10.1007/s11481-010-9236-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11481-010-9236-5

Keywords

Search

Navigation