Pellino 1 promotes lymphomagenesis by deregulating BCL6 polyubiquitination
Hye-Young Park, … , Doo Hyun Chung, Chang-Woo Lee
Hye-Young Park, … , Doo Hyun Chung, Chang-Woo Lee
Published October 8, 2014
Citation Information: J Clin Invest. 2014;124(11):4976-4988. https://doi.org/10.1172/JCI75667.
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Research Article Vascular biology

Pellino 1 promotes lymphomagenesis by deregulating BCL6 polyubiquitination

Abstract

The signal-responsive E3 ubiquitin ligase pellino 1 (PELI1) regulates TLR and T cell receptor (TCR) signaling and contributes to the maintenance of autoimmunity; however, little is known about the consequence of mutations that result in upregulation of PELI1. Here, we developed transgenic mice that constitutively express human PELI1 and determined that these mice have a shorter lifespan due to tumor formation. Constitutive expression of PELI1 resulted in ligand-independent hyperactivation of B cells and facilitated the development of a wide range of lymphoid tumors, with prominent B cell infiltration observed across multiple organs. PELI1 directly interacted with the oncoprotein B cell chronic lymphocytic leukemia (BCL6) and induced lysine 63–mediated BCL6 polyubiquitination. In samples from patients with diffuse large B cell lymphomas (DLBCLs), PELI1 expression levels positively correlated with BCL6 expression, and PELI1 overexpression was closely associated with poor prognosis in DLBCLs. Together, these results suggest that increased PELI1 expression and subsequent induction of BCL6 promotes lymphomagenesis and that this pathway may be a potential target for therapeutic strategies to treat B cell lymphomas.

Authors

Hye-Young Park, Heounjeong Go, Ha Rim Song, Suhyeon Kim, Geun-Hyoung Ha, Yoon-Kyung Jeon, Ji-Eun Kim, Ho Lee, Hyeseong Cho, Ho Chul Kang, Hee-Young Chung, Chul-Woo Kim, Doo Hyun Chung, Chang-Woo Lee

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Figure 4

PELI1 interacts with and induces K63-mediated BCL6 polyubiquitination.

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PELI1 interacts with and induces K63-mediated BCL6 polyubiquitination. (...
(A) RL7 cells were stimulated or not with LPS for 24 hours, and lysates were incubated with GST or GST-PELI1. Bound proteins were resolved by SDS-PAGE and immunoblotted with anti-BCL6 and anti–c-Rel antibodies. Asterisk denotes nonspecific band. (B) RL7 cell lysates were immunoprecipitated with anti-PELI1 antibody and immunoblotted with anti-BCL6 and anti-PELI1 antibodies. Asterisk denotes nonspecific band. (C) GST (lower arrow) or GST-BCL6 (upper arrow) was incubated with purified His-PELI1 and subjected to immunoblotting with anti-BCL6 and anti-PELI1 antibodies. CS, Coomassie brilliant blue staining. (D) HeLa cells were transfected with Myc-PELI1-FL or Myc-PELI1-ΔC in combination with HA-Ub and HA-BCL6 expression plasmids. At 24 hours after transfection, cells were treated with LPS for 24 hours and harvested for immunoprecipitation with an anti-BCL6 antibody. The BCL6 protein complex was subjected to immunoblotting with an anti-Ub antibody. (E) Purified GST or GST-BCL6 was incubated with purified His-PELI1-FL or His-PELI1-ΔC in conjunction with E1, E2, and HA-Ub enzymes. Reaction mixtures were immunoblotted with an anti-BCL6 antibody. (F) RL7 cells were transfected with Myc-PELI1 or pMyc and HA-Ub K63 expression plasmids. At 24 hours after transfection, cells were treated with LPS and harvested for immunoprecipitation with an anti-BCL6 antibody. The BCL6 protein complex was subjected to immunoblotting with an anti-HA antibody. (G) Purified GST or GST-BCL6 was incubated with purified His-PELI1 in conjunction with E1, E2, and HA-Ub K63 enzymes. Reaction mixtures were immunoblotted with an anti-BCL6 antibody.