N-terminal α-amino SUMOylation of cofilin-1 is critical for its regulation of actin depolymerization

Weiji Weng, Xiaokun Gu, Yang Yang, Qiao Zhang, Qi Deng, Jie Zhou, Jinke Cheng, Michael X. Zhu, Junfeng Feng (), Ou Huang () and Yong Li ()
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Weiji Weng: Shanghai Jiao Tong University School of Medicine
Xiaokun Gu: Shanghai Jiao Tong University School of Medicine
Yang Yang: Shanghai Jiao Tong University School of Medicine
Qiao Zhang: Shanghai Jiao Tong University School of Medicine
Qi Deng: Shanghai Jiao Tong University School of Medicine
Jie Zhou: Shanghai Jiao Tong University School of Medicine
Jinke Cheng: Shanghai Jiao Tong University School of Medicine
Michael X. Zhu: The University of Texas Health Science Center at Houston
Junfeng Feng: Shanghai Jiao Tong University School of Medicine
Ou Huang: Shanghai Jiao Tong University School of Medicine
Yong Li: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Small ubiquitin-like modifier (SUMO) typically conjugates to target proteins through isopeptide linkage to the ε-amino group of lysine residues. This posttranslational modification (PTM) plays pivotal roles in modulating protein function. Cofilins are key regulators of actin cytoskeleton dynamics and are well-known to undergo several different PTMs. Here, we show that cofilin-1 is conjugated by SUMO1 both in vitro and in vivo. Using mass spectrometry and biochemical and genetic approaches, we identify the N-terminal α-amino group as the SUMO-conjugation site of cofilin-1. Common to conventional SUMOylation is that the N-α-SUMOylation of cofilin-1 is also mediated by SUMO activating (E1), conjugating (E2), and ligating (E3) enzymes and reversed by the SUMO deconjugating enzyme, SENP1. Specific to the N-α-SUMOylation is the physical association of the E1 enzyme to the substrate, cofilin-1. Using F-actin co-sedimentation and actin depolymerization assays in vitro and fluorescence staining of actin filaments in cells, we show that the N-α-SUMOylation promotes cofilin-1 binding to F-actin and cofilin-induced actin depolymerization. This covalent conjugation by SUMO at the N-α amino group of cofilin-1, rather than at an internal lysine(s), serves as an essential PTM to tune cofilin-1 function during regulation of actin dynamics.

Date: 2023
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DOI: 10.1038/s41467-023-41520-2

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