Micropeptide ASAP encoded by LINC00467 promotes colorectal cancer progression by directly modulating ATP synthase activity
Qiwei Ge, … , Shujie Chen, Liangjing Wang
Qiwei Ge, … , Shujie Chen, Liangjing Wang
Published September 30, 2021
Citation Information: J Clin Invest. 2021;131(22):e152911. https://doi.org/10.1172/JCI152911.
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Research Article Gastroenterology Oncology

Micropeptide ASAP encoded by LINC00467 promotes colorectal cancer progression by directly modulating ATP synthase activity

Abstract

Emerging evidence has shown that open reading frames inside long noncoding RNAs (lncRNAs) could encode micropeptides. However, their roles in cellular energy metabolism and tumor progression remain largely unknown. Here, we identified a 94 amino acid–length micropeptide encoded by lncRNA LINC00467 in colorectal cancer. We also characterized its conservation across higher mammals, localization to mitochondria, and the concerted local functions. This peptide enhanced the ATP synthase construction by interacting with the subunits α and γ (ATP5A and ATP5C), increased ATP synthase activity and mitochondrial oxygen consumption rate, and thereby promoted colorectal cancer cell proliferation. Hence, this micropeptide was termed ATP synthase–associated peptide (ASAP). Furthermore, loss of ASAP suppressed patient-derived xenograft growth with attenuated ATP synthase activity and mitochondrial ATP production. Clinically, high expression of ASAP and LINC00467 predicted poor prognosis of colorectal cancer patients. Taken together, our findings revealed a colorectal cancer–associated micropeptide as a vital player in mitochondrial metabolism and provided a therapeutic target for colorectal cancer.

Authors

Qiwei Ge, Dingjiacheng Jia, Dong Cen, Yadong Qi, Chengyu Shi, Junhong Li, Lingjie Sang, Luo-jia Yang, Jiamin He, Aifu Lin, Shujie Chen, Liangjing Wang

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Figure 6

Identification of key residues that contribute to ASAP-ATP synthase interaction.

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Identification of key residues that contribute to ASAP-ATP synthase inte...
(A) WT or mutant ASAP was cooverexpressed with SFB-ATP5A in HEK293T cells. Co-IP assays showed that K79A mutation on ASAP abolished the interaction between ASAP and ATP5A. (B) WT or mutant ASAP was cooverexpressed with SFB-ATP5C in HEK293T cells. Co-IP assays showed that D65A mutation on ASAP abolished the interaction between ASAP and ATP5C. (C) WT or mutant SFB-ATP5A was cooverexpressed with ASAP-His in HEK293T cells. Co-IP assays showed that D454A mutation on ATP5A abolished the interaction between ASAP and ATP5A. (D) WT or mutant SFB-ATP5C was cooverexpressed with ASAP-His in HEK293T cells. Co-IP assays showed that K197A mutation on ATP5C abolished the interaction between ASAP and ATP5C. (E) The endogenous interaction between ATP5A and ATP5C in HCT116 and RKO cells with ASAP overexpressed or Mut-ASAP was investigated using Co-IP assays. (F) The endogenous interaction between ATP5A and ATP5C in HCT116 and RKO cells with ASAP KO or ASAP restored was investigated using Co-IP assays. (G) In vitro pulldown assays were performed using bacterial purified MBP-ATP5A-His and GST-ATP5C in the presence of WT ASAP or mutant ASAP. Data are representative of 3 independent experiments (A–G).