TY - JOUR
T1 - An actin filament branching surveillance system regulates cell cycle progression, cytokinesis and primary ciliogenesis
AU - Cao, Muqing
AU - Zou, Xiaoxiao
AU - Li, Chaoyi
AU - Lin, Zaisheng
AU - Wang, Ni
AU - Zou, Zhongju
AU - Ye, Youqiong
AU - Seemann, Joachim
AU - Levine, Beth
AU - Tang, Zaiming
AU - Zhong, Qing
N1 - Funding Information:
We thank the Core facility of Basic Medical Science at the Shanghai Jiao Tong University School of Medicine for technical support. We thank Drs. William Snell (University of Maryland), Junmin Pan (Tsinghua University), and Saikat Mukhopadhyay (University of Texas Southwestern Medical Center) for their insightful discussions, Dr. Rolf Brekken (University of Texas Southwestern Medical Center) for technical advice, Andrew Shiau (Ludwig Institute for Cancer Research, San Diego) for kindly providing centrinone, and Meng-Fu Bryan Tsou (Memorial Sloan Kettering Cancer Center) for kindly providing cell lines for preliminary tests. This work was supported, in part, by National Natural Science Foundation of China (91957204, 92254307, 91754205, 31771523) to Q.Z., Mobility program M-0140 to Q.Z., Ministry of Science and Technology of China (2019YFA0508602) to Q.Z., Program of Shanghai Subject Chief Scientist (19XD1402200) to Q.Z., Shanghai Municipal Science and Technology Project (20JC1411100), Ministry of Science and Technology of China (2021YFC2700800) to M.C., National Natural Science Foundation of China (91954123, 31972887) to M.C., Grants from the State Key Laboratory of Oncogenes and Related Genes to M.C., Clinical research projects of Shanghai Municipal Health Commission (20194Y0133) to M.C., National Natural Science Foundation of China (31500627, 32070741) to Z.T., Shanghai Municipal Science and Technology Project (20ZR1430300) to Z.T., NIH (GM096070) to J.S., Welch Foundation (I-1910) to J.S., and Cancer Prevention Research Institute of Texas (CPRIT) grant RP120718 to B.L.. This work was also supported by Shanghai Frontier Science Center of Cellular Homeostasis and Human Diseases and innovative research team of high-level local universities in Shanghai (SHSMU-ZDCX20211800 and SHSMU-ZDCX20211801).
Funding Information:
We thank the Core facility of Basic Medical Science at the Shanghai Jiao Tong University School of Medicine for technical support. We thank Drs. William Snell (University of Maryland), Junmin Pan (Tsinghua University), and Saikat Mukhopadhyay (University of Texas Southwestern Medical Center) for their insightful discussions, Dr. Rolf Brekken (University of Texas Southwestern Medical Center) for technical advice, Andrew Shiau (Ludwig Institute for Cancer Research, San Diego) for kindly providing centrinone, and Meng-Fu Bryan Tsou (Memorial Sloan Kettering Cancer Center) for kindly providing cell lines for preliminary tests. This work was supported, in part, by National Natural Science Foundation of China (91957204, 92254307, 91754205, 31771523) to Q.Z., Mobility program M-0140 to Q.Z., Ministry of Science and Technology of China (2019YFA0508602) to Q.Z., Program of Shanghai Subject Chief Scientist (19XD1402200) to Q.Z., Shanghai Municipal Science and Technology Project (20JC1411100), Ministry of Science and Technology of China (2021YFC2700800) to M.C., National Natural Science Foundation of China (91954123, 31972887) to M.C., Grants from the State Key Laboratory of Oncogenes and Related Genes to M.C., Clinical research projects of Shanghai Municipal Health Commission (20194Y0133) to M.C., National Natural Science Foundation of China (31500627, 32070741) to Z.T., Shanghai Municipal Science and Technology Project (20ZR1430300) to Z.T., NIH (GM096070) to J.S., Welch Foundation (I-1910) to J.S., and Cancer Prevention Research Institute of Texas (CPRIT) grant RP120718 to B.L. This work was also supported by Shanghai Frontier Science Center of Cellular Homeostasis and Human Diseases and innovative research team of high-level local universities in Shanghai (SHSMU-ZDCX20211800 and SHSMU-ZDCX20211801).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - Dysfunction of cell cycle control and defects of primary ciliogenesis are two features of many cancers. Whether these events are interconnected and the driving mechanism coordinating them remains elusive. Here, we identify an actin filament branching surveillance system that alerts cells of actin branching insufficiency and regulates cell cycle progression, cytokinesis and primary ciliogenesis. We find that Oral-Facial-Digital syndrome 1 functions as a class II Nucleation promoting factor to promote Arp2/3 complex-mediated actin branching. Perturbation of actin branching promotes OFD1 degradation and inactivation via liquid-to-gel transition. Elimination of OFD1 or disruption of OFD1-Arp2/3 interaction drives proliferating, non-transformed cells into quiescence with ciliogenesis by an RB-dependent mechanism, while it leads oncogene-transformed/cancer cells to incomplete cytokinesis and irreversible mitotic catastrophe via actomyosin ring malformation. Inhibition of OFD1 leads to suppression of multiple cancer cell growth in mouse xenograft models. Thus, targeting OFD1-mediated actin filament branching surveillance system provides a direction for cancer therapy.
AB - Dysfunction of cell cycle control and defects of primary ciliogenesis are two features of many cancers. Whether these events are interconnected and the driving mechanism coordinating them remains elusive. Here, we identify an actin filament branching surveillance system that alerts cells of actin branching insufficiency and regulates cell cycle progression, cytokinesis and primary ciliogenesis. We find that Oral-Facial-Digital syndrome 1 functions as a class II Nucleation promoting factor to promote Arp2/3 complex-mediated actin branching. Perturbation of actin branching promotes OFD1 degradation and inactivation via liquid-to-gel transition. Elimination of OFD1 or disruption of OFD1-Arp2/3 interaction drives proliferating, non-transformed cells into quiescence with ciliogenesis by an RB-dependent mechanism, while it leads oncogene-transformed/cancer cells to incomplete cytokinesis and irreversible mitotic catastrophe via actomyosin ring malformation. Inhibition of OFD1 leads to suppression of multiple cancer cell growth in mouse xenograft models. Thus, targeting OFD1-mediated actin filament branching surveillance system provides a direction for cancer therapy.
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U2 - 10.1038/s41467-023-37340-z
DO - 10.1038/s41467-023-37340-z
M3 - Article
C2 - 36973243
AN - SCOPUS:85150958055
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1687
ER -