Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis

Ursula Baumann; Vanesa Fernández-Saíz; Martina Rudelius; Simone Lemeer; Roland Rad; Anna Maria Knorn; Jolanta Slawska; Katharina Engel; Irmela Jeremias; Zhoulei Li; Viktoriya Tomiatti; Anna Lena Illert; Bianca Sabrina Targosz; Martin Braun; Sven Perner; Michael Leitges; Wolfram Klapper; Martin Dreyling; Cornelius Miething; Georg Lenz; Andreas Rosenwald; Christian Peschel; Ulrich Keller; Bernhard Kuster; Florian Bassermann

doi:10.1038/nm.3740

Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis

Ursula Baumann, Vanesa Fernández-Saíz, Martina Rudelius, Simone Lemeer, Roland Rad, Anna Maria Knorn, Jolanta Slawska, Katharina Engel, Irmela Jeremias, Zhoulei Li, Viktoriya Tomiatti, Anna Lena Illert, Bianca Sabrina Targosz, Martin Braun, Sven Perner, Michael Leitges, Wolfram Klapper, Martin Dreyling, Cornelius Miething, Georg LenzAndreas Rosenwald, Christian Peschel, Ulrich Keller, Bernhard Kuster, Florian Bassermann

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Abstract

We searched for genetic alterations in human B cell lymphoma that affect the ubiquitin-proteasome system. This approach identified FBXO25 within a minimal common region of frequent deletion in mantle cell lymphoma (MCL). FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box) FBXO25 ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase CÎ (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1. Our analyses in primary human MCL identify monoallelic loss of FBXO25 and stabilizing HAX1 phosphodegron mutations. Accordingly, FBXO25 re-expression in FBXO25-deleted MCL cells promotes cell death, whereas expression of the HAX-1 phosphodegron mutant inhibits apoptosis. In addition, knockdown of FBXO25 significantly accelerated lymphoma development in EÎ 1/4-Myc mice and in a human MCL xenotransplant model. Together we identify a PRKCD-dependent proapoptotic mechanism controlling HAX-1 stability, and we propose that FBXO25 functions as a haploinsufficient tumor suppressor and that HAX1 is a proto-oncogene in MCL.

Original language	English
Pages (from-to)	1401-1409
Number of pages	9
Journal	Nature Medicine
Volume	20
Issue number	12
DOIs	https://doi.org/10.1038/nm.3740
State	Published - 1 Dec 2014

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Baumann, U., Fernández-Saíz, V., Rudelius, M., Lemeer, S., Rad, R., Knorn, A. M., Slawska, J., Engel, K., Jeremias, I., Li, Z., Tomiatti, V., Illert, A. L., Targosz, B. S., Braun, M., Perner, S., Leitges, M., Klapper, W., Dreyling, M., Miething, C., ... Bassermann, F. (2014). Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis. Nature Medicine, 20(12), 1401-1409. https://doi.org/10.1038/nm.3740

@article{7d19c0aa41e94c32bdd6a1375b92de8a,

title = "Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis",

abstract = "We searched for genetic alterations in human B cell lymphoma that affect the ubiquitin-proteasome system. This approach identified FBXO25 within a minimal common region of frequent deletion in mantle cell lymphoma (MCL). FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box) FBXO25 ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase C{\^I} (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1. Our analyses in primary human MCL identify monoallelic loss of FBXO25 and stabilizing HAX1 phosphodegron mutations. Accordingly, FBXO25 re-expression in FBXO25-deleted MCL cells promotes cell death, whereas expression of the HAX-1 phosphodegron mutant inhibits apoptosis. In addition, knockdown of FBXO25 significantly accelerated lymphoma development in E{\^I} 1/4-Myc mice and in a human MCL xenotransplant model. Together we identify a PRKCD-dependent proapoptotic mechanism controlling HAX-1 stability, and we propose that FBXO25 functions as a haploinsufficient tumor suppressor and that HAX1 is a proto-oncogene in MCL.",

author = "Ursula Baumann and Vanesa Fern{\'a}ndez-Sa{\'i}z and Martina Rudelius and Simone Lemeer and Roland Rad and Knorn, {Anna Maria} and Jolanta Slawska and Katharina Engel and Irmela Jeremias and Zhoulei Li and Viktoriya Tomiatti and Illert, {Anna Lena} and Targosz, {Bianca Sabrina} and Martin Braun and Sven Perner and Michael Leitges and Wolfram Klapper and Martin Dreyling and Cornelius Miething and Georg Lenz and Andreas Rosenwald and Christian Peschel and Ulrich Keller and Bernhard Kuster and Florian Bassermann",

year = "2014",

month = dec,

day = "1",

doi = "10.1038/nm.3740",

language = "English",

volume = "20",

pages = "1401--1409",

journal = "Nature Medicine",

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Baumann, U, Fernández-Saíz, V, Rudelius, M, Lemeer, S, Rad, R, Knorn, AM, Slawska, J, Engel, K, Jeremias, I, Li, Z, Tomiatti, V, Illert, AL, Targosz, BS, Braun, M, Perner, S, Leitges, M, Klapper, W, Dreyling, M, Miething, C, Lenz, G, Rosenwald, A, Peschel, C, Keller, U, Kuster, B & Bassermann, F 2014, 'Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis', Nature Medicine, vol. 20, no. 12, pp. 1401-1409. https://doi.org/10.1038/nm.3740

TY - JOUR

T1 - Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis

AU - Baumann, Ursula

AU - Fernández-Saíz, Vanesa

AU - Rudelius, Martina

AU - Lemeer, Simone

AU - Rad, Roland

AU - Knorn, Anna Maria

AU - Slawska, Jolanta

AU - Engel, Katharina

AU - Jeremias, Irmela

AU - Li, Zhoulei

AU - Tomiatti, Viktoriya

AU - Illert, Anna Lena

AU - Targosz, Bianca Sabrina

AU - Braun, Martin

AU - Perner, Sven

AU - Leitges, Michael

AU - Klapper, Wolfram

AU - Dreyling, Martin

AU - Miething, Cornelius

AU - Lenz, Georg

AU - Rosenwald, Andreas

AU - Peschel, Christian

AU - Keller, Ulrich

AU - Kuster, Bernhard

AU - Bassermann, Florian

PY - 2014/12/1

Y1 - 2014/12/1

N2 - We searched for genetic alterations in human B cell lymphoma that affect the ubiquitin-proteasome system. This approach identified FBXO25 within a minimal common region of frequent deletion in mantle cell lymphoma (MCL). FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box) FBXO25 ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase CÎ (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1. Our analyses in primary human MCL identify monoallelic loss of FBXO25 and stabilizing HAX1 phosphodegron mutations. Accordingly, FBXO25 re-expression in FBXO25-deleted MCL cells promotes cell death, whereas expression of the HAX-1 phosphodegron mutant inhibits apoptosis. In addition, knockdown of FBXO25 significantly accelerated lymphoma development in EÎ 1/4-Myc mice and in a human MCL xenotransplant model. Together we identify a PRKCD-dependent proapoptotic mechanism controlling HAX-1 stability, and we propose that FBXO25 functions as a haploinsufficient tumor suppressor and that HAX1 is a proto-oncogene in MCL.

AB - We searched for genetic alterations in human B cell lymphoma that affect the ubiquitin-proteasome system. This approach identified FBXO25 within a minimal common region of frequent deletion in mantle cell lymphoma (MCL). FBXO25 encodes an orphan F-box protein that determines the substrate specificity of the SCF (SKP1-CUL1-F-box) FBXO25 ubiquitin ligase complex. An unbiased screen uncovered the prosurvival protein HCLS1-associated protein X-1 (HAX-1) as the bona fide substrate of FBXO25 that is targeted after apoptotic stresses. Protein kinase CÎ (PRKCD) initiates this process by phosphorylating FBXO25 and HAX-1, thereby spatially directing nuclear FBXO25 to mitochondrial HAX-1. Our analyses in primary human MCL identify monoallelic loss of FBXO25 and stabilizing HAX1 phosphodegron mutations. Accordingly, FBXO25 re-expression in FBXO25-deleted MCL cells promotes cell death, whereas expression of the HAX-1 phosphodegron mutant inhibits apoptosis. In addition, knockdown of FBXO25 significantly accelerated lymphoma development in EÎ 1/4-Myc mice and in a human MCL xenotransplant model. Together we identify a PRKCD-dependent proapoptotic mechanism controlling HAX-1 stability, and we propose that FBXO25 functions as a haploinsufficient tumor suppressor and that HAX1 is a proto-oncogene in MCL.

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U2 - 10.1038/nm.3740

DO - 10.1038/nm.3740

M3 - Article

C2 - 25419709

AN - SCOPUS:84925581491

SN - 1078-8956

VL - 20

SP - 1401

EP - 1409

JO - Nature Medicine

JF - Nature Medicine

IS - 12

ER -

Disruption of the PRKCD-FBXO25-HAX-1 axis attenuates the apoptotic response and drives lymphomagenesis

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