Regulation of B cell receptor-dependent NF-κB signaling by the tumor suppressor KLHL14

Proceedings of the National Academy of Sciences of the United States of America
Jaewoo ChoiLouis M Staudt

Abstract

The KLHL14 gene acquires frequent inactivating mutations in mature B cell malignancies, especially in the MYD88L265P, CD79B mutant (MCD) genetic subtype of diffuse large B cell lymphoma (DLBCL), which relies on B cell receptor (BCR) signaling for survival. However, the pathogenic role of KLHL14 in DLBCL and its molecular function are largely unknown. Here, we report that KLHL14 is in close proximity to the BCR in the endoplasmic reticulum of MCD cell line models and promotes the turnover of immature glycoforms of BCR subunits, reducing total cellular BCR levels. Loss of KLHL14 confers relative resistance to the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and promotes assembly of the MYD88-TLR9-BCR (My-T-BCR) supercomplex, which initiates prosurvival NF-κB activation. Consequently, KLHL14 inactivation allows MCD cells to maintain NF-κB signaling in the presence of ibrutinib. These findings reinforce the central role of My-T-BCR-dependent NF-κB signaling in MCD DLBCL and suggest that the genetic status of KLHL14 should be considered in clinical trials testing inhibitors of BTK and BCR signaling mediators in DLBCL.

References

Feb 3, 2005·Nature Reviews. Molecular Cell Biology·Matthew D Petroski, Raymond J Deshaies
Oct 7, 2005·Genome Biology·Peter J StogiosGilbert G Privé
Sep 20, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Miao ZhangMarcus R Clark
Oct 28, 2008·Computer Methods and Programs in Biomedicine·A Allalou, C Wählby
Jun 19, 2009·The Journal of Biological Chemistry·Lisa M GilesLih-Shen Chin
Nov 26, 2010·Current Protocols in Protein Science·Hudson H Freeze, Christian Kranz
Dec 24, 2010·Nature·Vu N NgoLouis M Staudt
Jan 25, 2011·Journal of Proteome Research·Jürgen CoxMatthias Mann
Jul 14, 2011·Nature Communications·Flávia C NeryXandra O Breakefield
Jun 30, 2012·Nature Methods·Johannes SchindelinAlbert Cardona
Sep 21, 2013·Nature Protocols·Namrata D UdeshiSteven A Carr
May 2, 2015·Annals of the New York Academy of Sciences·Karen M Haas
Jun 4, 2015·Molecular Systems Biology·Shankha SatpathyChunaram Choudhary
Jul 21, 2015·Nature Medicine·Wyndham H WilsonLouis M Staudt
Oct 21, 2015·Proceedings of the National Academy of Sciences of the United States of America·Ryan M YoungLouis M Staudt
Jan 19, 2016·Nature Biotechnology·John G DoenchDavid E Root
May 8, 2016·Proceedings of the National Academy of Sciences of the United States of America·Jasmin CorsoThomas Oellerich
Jun 28, 2016·Nature Methods·Stefka TyanovaJürgen Cox
May 30, 2017·Cancer Cell·Michail S LionakisWyndham H Wilson
Nov 17, 2017·The Journal of Experimental Medicine·Margaret VeselitsMarcus R Clark
Apr 12, 2018·The New England Journal of Medicine·Roland SchmitzLouis M Staudt
Jun 22, 2018·Nature·James D PhelanLouis M Staudt
Jun 26, 2018·International Immunology·Shuyin LiJi-Yang Wang
Feb 20, 2019·Methods in Molecular Biology·Daniel E WebsterJames D Phelan
Aug 24, 2019·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Xiaoxian ShiMeidan Ying
Sep 21, 2019·The Journal of Cell Biology·Zhihao Sun, Jeffrey L Brodsky

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