Cytoplasmic FANCA-FANCC complex interacts and stabilizes the cytoplasm-dislocalized leukemic nucleophosmin protein (NPMc).
Eight of the Fanconi anemia (FA) proteins form a core complex that activates the FA pathway. Some core complex components also form subcomplexes for yet-to-be-elucidated functions. Here, we have analyzed the interaction between a cytoplasmic FA subcomplex and the leukemic nucleophosmin (NPMc). Exogenous NPMc was degraded rapidly in FA acute myeloid leukemia bone marrow cells. Knockdown of FANCA or FANCC in leukemic OCI/AML3 cells induced rapid degradation of endogenous NPMc. NPMc degradation was mediated by the ubiquitin-proteasome pathway involving the IBR-type RING-finger E3 ubiquitin ligase IBRDC2, and genetic correction of FA-A or FA-C lymphoblasts prevented NPMc ubiquitination. Moreover, cytoplasmic FANCA and FANCC formed a cytoplasmic complex and interacted with NPMc. Using a patient-derived FANCC mutant and a nuclearized FANCC, we demonstrated that the cytoplasmic FANCA-FANCC complex was essential for NPMc stability. Finally, depletion of FANCA and FANCC in NPMc-positive leukemic cells significantly increased inflammation and chemoresistance through NF-κB activation. Our findings not only reveal the molecular mechanism involving cytoplasmic retention of NPMc but also suggest cytoplasmic function of FANCA and FANCC in NPMc-related leukemogenesis.
Du
Wei
W
Division of Experimental Hematology and Cancer Biology, the Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Li
Jie
J
Sipple
Jared
J
Chen
Jianjun
J
Pang
Qishen
Q
D001483:Base Sequence; D045744:Cell Line, Tumor; D003593:Cytoplasm / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D005199:Fanconi Anemia / Q000235:genetics / Q000378:metabolism; D052217:Fanconi Anemia Complementation Group A Protein / Q000235:genetics / Q000378:metabolism*; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D011485:Protein Binding; D055550:Protein Stability; D021381:Protein Transport; D054875:Ubiquitination
D052217:Fanconi Anemia Complementation Group A Protein; D052218:Fanconi Anemia Complementation Group C Protein; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin