Abstract
PRKCD promotes HAX1 degradation by FBXO25 to induce apoptosis and inhibit B-cell lymphomagenesis.
Major finding: PRKCD promotes HAX1 degradation by FBXO25 to induce apoptosis and inhibit B-cell lymphomagenesis.
Mechanism: Phosphorylation of FBXO25 and HAX1 by PRKCD directs FBXO25 to the mitochondria for HAX1 degradation.
Impact: Recurrent monoallelic FBXO25 deletions and stabilizing HAX1 mutations are present in human MCL.
Proper regulation of apoptosis is critical for B-cell development and homeostasis, and disruption of proapoptotic signaling has been implicated as a driving mechanism in lymphomagenesis. Baumann, Fernández-Sáiz, and colleagues investigated genetic alterations that affect the ubiquitin–proteasome pathway in human B-cell lymphoma and identified monoallelic deletions of the gene encoding the orphan F-box protein 25 (FBXO25), which determines the substrate specificity of the SKP1–CUL1–F-boxFBXO25 ubiquitin ligase complex, in mantle cell lymphoma (MCL). An unbiased screen revealed that FBXO25 stimulated apoptosis via binding to the mitochondrial prosurvival protein HCLS1-associated protein X-1 (HAX1) and targeting HAX1 for ubiquitination and proteasome-mediated degradation in response to apoptotic stimuli. Induction of apoptosis by etoposide stimulated translocation of FBXO25 from the nucleus to the mitochondria, where it colocalized with HAX1 in a phosphorylation-dependent manner. Phosphorylation of FBXO25 at Ser178 within its nuclear export signal and of HAX1 at Ser210 within its degron motif by protein kinase C (PKC) δ (PRKCD), the only known proapoptotic PKC isoform, was required for FBXO25 translocation, HAX1 degradation, and etoposide-induced apoptosis. Depletion of FBXO25 accelerated lymphoma development and decreased survival in the Eμ-MYC mouse model and a xenotransplant model of human MCL, whereas overexpression of FBXO25 had the opposite effect. Consistent with these findings, human MCL cell lines with FBXO25 deletions exhibited increased resistance to apoptotic stimuli, and reconstitution of FBXO25 restored the apoptotic response in these cells. Furthermore, analysis of primary human MCL samples revealed an inverse correlation in FBXO25 and HAX1 expression, as well as mutually exclusive monoallelic deletions of FBXO25 and stabilizing HAX1mutations affecting Ser210. These data indicate that disruption of PRKCD–FBXO25-mediated apoptosis contributes to lymphomagenesis and suggest HAX1 as a potential therapeutic target for MCL.
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