Regulation of mitochondrial fission by GIPC-mediated Drp1 retrograde transport

被引:14
作者
Ramonett, Aaron [1 ]
Kwak, Eun-A [1 ]
Ahmed, Tasmia [2 ]
Flores, Paola Cruz [2 ]
Ortiz, Hannah R. [1 ]
Lee, Yeon Sun [1 ]
Vanderah, Todd W. [1 ]
Largent-Milnes, Tally [1 ]
Kashatus, David F. [5 ]
Langlais, Paul R. [3 ]
Mythreye, Karthikeyan [6 ]
Lee, Nam Y. [1 ,2 ,4 ]
机构
[1] Univ Arizona, Dept Pharmacol, Tucson, AZ 85724 USA
[2] Univ Arizona, Dept Chem & Biochem, Tucson, AZ 85724 USA
[3] Univ Arizona, Dept Med, Tucson, AZ 85724 USA
[4] Univ Arizona, Canc Ctr, Tucson, AZ 85724 USA
[5] Univ Virginia, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA 22908 USA
[6] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA
关键词
DYNAMIN-RELATED PROTEIN-1; MYOSIN-VI; PHOSPHORYLATION; RECRUITMENT; FUSION; MFF; GIPC/SYNECTIN; PERINUCLEAR; HOMEOSTASIS; INHIBITION;
D O I
10.1091/mbc.E21-06-0286
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission, a large cytoplasmic GTPase recruited to the mitochondrial surface via transmembrane adaptors to initiate scission. While Brownian motion likely accounts for the local interactions between Drp1 and the mitochondrial adaptors, how this essential enzyme is targeted from more distal regions like the cell periphery remains unknown. Based on proteomic interactome screening and cell-based studies, we report that GAIP/RGS19-interacting protein (GIPC) mediates the actin-based retrograde transport of Drp1 toward the perinuclear mitochondria to enhance fission. Drp1 interacts with GIPC through its atypical C-terminal PDZ-binding motif. Loss of this interaction abrogates Drp1 retrograde transport resulting in cytoplasmic mislocalization and reduced fission despite retaining normal intrinsic GTPase activity. Functionally, we demonstrate that GIPC potentiates the Drp1-driven proliferative and migratory capacity in cancer cells. Together, these findings establish a direct molecular link between altered GIPC expression and Drp1 function in cancer progression and metabolic disorders.
引用
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页数:13
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