Human T-Cell Leukemia Virus Type 1 (HTLV-1) Tax Requires CADM1/TSLC1 for Inactivation of the NF-κB Inhibitor A20 and Constitutive NF-κB Signaling

Rajeshree Pujari, Richard Hunte, Remy Thomas, Louise van der Weyden, Dan Rauch, Lee Ratner, Jennifer K. Nyborg, Juan Carlos Ramos, Yoshimi Takai, Noula Shembade

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Persistent activation of NF-κB by the Human T-cell leukemia virus type 1 (HTLV-1) oncoprotein, Tax, is vital for the development and pathogenesis of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). K63-linked polyubiquitinated Tax activates the IKK complex in the plasma membrane-associated lipid raft microdomain. Tax also interacts with TAX1BP1 to inactivate the NF-κB negative regulatory ubiquitin-editing A20 enzyme complex. However, the molecular mechanisms of Tax-mediated IKK activation and A20 protein complex inactivation are poorly understood. Here, we demonstrated that membrane associated CADM1 (Cell adhesion molecule1) recruits Ubc13 to Tax, causing K63-linked polyubiquitination of Tax, and IKK complex activation in the membrane lipid raft. The c-terminal cytoplasmic tail containing PDZ binding motif of CADM1 is critical for Tax to maintain persistent NF-κB activation. Finally, Tax failed to inactivate the NF-κB negative regulator ubiquitin-editing enzyme A20 complex, and activate the IKK complex in the lipid raft in absence of CADM1. Our results thus indicate that CADM1 functions as a critical scaffold molecule for Tax and Ubc13 to form a cellular complex with NEMO, TAX1BP1 and NRP, to activate the IKK complex in the plasma membrane-associated lipid rafts, to inactivate NF-κB negative regulators, and maintain persistent NF-κB activation in HTLV-1 infected cells.

Original languageEnglish
Article numbere1004721
Pages (from-to)1-27
Number of pages27
JournalPLoS Pathogens
Volume11
Issue number3
DOIs
Publication statusPublished - 1 Jan 2015
Externally publishedYes

Fingerprint

Deltaretrovirus
Cell Adhesion
Membrane Lipids
Ubiquitin
Cell Membrane
Tropical Spastic Paraparesis
Adult T Cell Leukemia Lymphoma
Spinal Cord Diseases
Oncogene Proteins
Enzymes
Lipids
Membranes
Proteins

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Human T-Cell Leukemia Virus Type 1 (HTLV-1) Tax Requires CADM1/TSLC1 for Inactivation of the NF-κB Inhibitor A20 and Constitutive NF-κB Signaling. / Pujari, Rajeshree; Hunte, Richard; Thomas, Remy; van der Weyden, Louise; Rauch, Dan; Ratner, Lee; Nyborg, Jennifer K.; Ramos, Juan Carlos; Takai, Yoshimi; Shembade, Noula.

In: PLoS Pathogens, Vol. 11, No. 3, e1004721, 01.01.2015, p. 1-27.

Research output: Contribution to journalArticle

Pujari, R, Hunte, R, Thomas, R, van der Weyden, L, Rauch, D, Ratner, L, Nyborg, JK, Ramos, JC, Takai, Y & Shembade, N 2015, 'Human T-Cell Leukemia Virus Type 1 (HTLV-1) Tax Requires CADM1/TSLC1 for Inactivation of the NF-κB Inhibitor A20 and Constitutive NF-κB Signaling', PLoS Pathogens, vol. 11, no. 3, e1004721, pp. 1-27. https://doi.org/10.1371/journal.ppat.1004721
Pujari, Rajeshree ; Hunte, Richard ; Thomas, Remy ; van der Weyden, Louise ; Rauch, Dan ; Ratner, Lee ; Nyborg, Jennifer K. ; Ramos, Juan Carlos ; Takai, Yoshimi ; Shembade, Noula. / Human T-Cell Leukemia Virus Type 1 (HTLV-1) Tax Requires CADM1/TSLC1 for Inactivation of the NF-κB Inhibitor A20 and Constitutive NF-κB Signaling. In: PLoS Pathogens. 2015 ; Vol. 11, No. 3. pp. 1-27.
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abstract = "Persistent activation of NF-κB by the Human T-cell leukemia virus type 1 (HTLV-1) oncoprotein, Tax, is vital for the development and pathogenesis of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). K63-linked polyubiquitinated Tax activates the IKK complex in the plasma membrane-associated lipid raft microdomain. Tax also interacts with TAX1BP1 to inactivate the NF-κB negative regulatory ubiquitin-editing A20 enzyme complex. However, the molecular mechanisms of Tax-mediated IKK activation and A20 protein complex inactivation are poorly understood. Here, we demonstrated that membrane associated CADM1 (Cell adhesion molecule1) recruits Ubc13 to Tax, causing K63-linked polyubiquitination of Tax, and IKK complex activation in the membrane lipid raft. The c-terminal cytoplasmic tail containing PDZ binding motif of CADM1 is critical for Tax to maintain persistent NF-κB activation. Finally, Tax failed to inactivate the NF-κB negative regulator ubiquitin-editing enzyme A20 complex, and activate the IKK complex in the lipid raft in absence of CADM1. Our results thus indicate that CADM1 functions as a critical scaffold molecule for Tax and Ubc13 to form a cellular complex with NEMO, TAX1BP1 and NRP, to activate the IKK complex in the plasma membrane-associated lipid rafts, to inactivate NF-κB negative regulators, and maintain persistent NF-κB activation in HTLV-1 infected cells.",
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AU - Thomas, Remy

AU - van der Weyden, Louise

AU - Rauch, Dan

AU - Ratner, Lee

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