title: Caspases cleave and inhibit the microRNA processing protein DiGeorge Critical Region 8.
abstract: DGCR8 (DiGeorge Critical Region 8) is an essential microRNA (miRNA) processing protein that recognizes primary transcripts of miRNAs (pri-miRNAs) and triggers their cleavage by the Drosha nuclease. We previously found that Fe(III) heme binds and activates DGCR8. Here we report that in HeLa cells, DGCR8 undergoes two proteolytic events that produce two C-terminal fragments called DGCR8(C1)  and DGCR8(C2) , respectively. DGCR8(C2)  accumulates during apoptosis and is generated through cleavage by a caspase. The caspase cleavage site is located in the central loop of the heme-binding domain. Cleavage of DGCR8 by caspase-3 in vitro results in loss of the otherwise tightly bound Fe(III) heme cofactor, dissociation of the N- and C-terminal proteolytic fragments, and inhibition of the pri-miRNA processing activity. These results reveal an intrinsic mechanism in the DGCR8 protein that seems to have evolved for regulating miRNA processing via association with Fe(III) heme and proteolytic cleavage by caspases. Decreased expression of miRNAs has been observed in apoptotic cells, and this change was attributed to caspase-mediated cleavage of a down-stream miRNA processing nuclease Dicer. We suggest that both the Drosha and Dicer cleavage steps of the miRNA maturation pathway may be inhibited in apoptosis and other biological processes where caspases are activated.
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Gong
authors.forename: Yanqiu
authors.initials: Y
authors.lastname: Chen
authors.forename: Rachel
authors.initials: R
authors.lastname: Senturia
authors.forename: Matthew
authors.initials: M
authors.lastname: Ulgherait
authors.forename: Michael
authors.initials: M
authors.lastname: Faller
authors.forename: Feng
authors.initials: F
authors.lastname: Guo
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D006367:HeLa Cells; D006418:Heme / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D008969:Molecular Sequence Data; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D059748:Proteolysis; D016601:RNA-Binding Proteins; D016415:Sequence Alignment
chemical_list: C474043:DGCR8 protein, human; D035683:MicroRNAs; D011506:Proteins; D016601:RNA-Binding Proteins; D006418:Heme; D020169:Caspases