Ubiquitination and translocation of TRAF2 is required for activation of JNK but not of p38 or NF-κB

Hasem Habelhah, Shoichi Takahashi, Ssang Goo Cho, Takayuki Kadoya, Toshiki Watanabe, Ze'ev Ronai

Research output: Contribution to journalArticlepeer-review

191 Scopus citations


TRAF2 is a RING finger protein that regulates the cellular response to stress and cytokines by controlling JNK, p38 and NF-κB signaling cascades. Here, we demonstrate that TRAF2 ubiquitination is required for TNFα-induced activation of JNK but not of p38 or NF-κB. Intact RING and zinc finger domains are required for TNFα-induced TRAF2 ubiquitination, which is also dependent on Ubc13. TRAF2 ubiquitination coincides with its translocation to the insoluble cellular fraction, resulting in selective activation of JNK. Inhibition of Ubc13 expression by RNAi resulted in inhibition of TNFα-induced TRAF2 translocation and impaired activation of JNK but not of IKK or p38. TRAF2 aggregates in the cytoplasm, as seen in Hodgkin-Reed-Sternberg lymphoma cells, resulting in constitutive NF-κB activity but failure to activate JNK. These findings demonstrate that the TRAF2 RING is required for Ubc13-dependent ubiquitination, resulting in translocation of TRAF2 to an insoluble fraction and activation of JNK, but not of p38 or NF-κB. Altogether, our findings highlight a novel mechanism of TRAF2-dependent activation of diverse signaling cascades that is impaired in Hodgkin-Reed-Sternberg cells.

Original languageEnglish
Pages (from-to)322-332
Number of pages11
JournalEMBO Journal
Issue number2
StatePublished - 28 Jan 2004


  • JNK
  • NFκB
  • TNFα
  • TRAF2
  • Ubiquitin


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