2. Academic Validation
  3. E3 Ubiquitin ligases Cbl-b and c-Cbl maintain the homeostasis of macrophages by regulating the M-CSF/M-CSFR signaling axis

E3 Ubiquitin ligases Cbl-b and c-Cbl maintain the homeostasis of macrophages by regulating the M-CSF/M-CSFR signaling axis

  • Cell Death Dis. 2025 Oct 7;16(1):716. doi: 10.1038/s41419-025-08047-4.
Fei Xu # 1,  Chensheng Tan # 1,  Kun Tang 1,  Guodong Qiao 1,  Yu Shao 1,  Xiaoping Li 1 2,  Ji Zhou 1,  Peijie Zhu 1,  Mengyun Wu 1,  Jiamin Cai 1,  Xiu Gao 1,  Yufeng Wang 3,  Beibei Huang 1,  Wenjun Wang 1,  Tian Xia 1,  Xuena Xu 3,  Jiaoyang Li 3,  Zhengrong Chen 3,  Yufang Shi 4,  Chuangli Hao 5,  Yi Yang 6,  Jinping Zhang 7
Affiliations

Affiliations

  • 1 Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
  • 2 Department of Clinical Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 3 Department of Respiratory Medicine, Children's Hospital of Soochow University, Suzhou, China.
  • 4 Institutes for Translational Medicine, Soochow University, Suzhou, China.
  • 5 Department of Respiratory Medicine, Children's Hospital of Soochow University, Suzhou, China. hcl_md@sina.com.
  • 6 Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China. yangyi87@suda.edu.cn.
  • 7 Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China. j_pzhang@suda.edu.cn.
  • # Contributed equally.
PMID: 41057360 DOI: 10.1038/s41419-025-08047-4
Abstract

The Casitas B-lineage lymphoma (Cbl) family proteins are E3 ubiquitin ligases implicated in the regulation of various immune cells. However, their function in macrophages remains unclear. Here, we identify both Cbl-b and c-Cbl (Cbls) as inhibitors of macrophage proliferation and promoters of macrophage Apoptosis. Mechanically, we identify that Cbls functions upstream of Akt and ERK to mediate the ubiquitination and degradation of M-CSFR. M-CSF stimulation promotes dimerization and autophosphorylation activation of M-CSFR on the macrophage membrane, thereby activating downstream PI3K-AKT and ERK signaling pathways, leading to different biological effects such as macrophage proliferation and survival. At the same time, the Y559 site of the M-CSFR undergoes autophosphorylation, which can promote receptor recruitment and phosphorylation of Cbls. This promotes Cbls to induce K63-linked polyubiquitination at the K791 site of M-CSFR, leading to internalization and degradation of M-CSFR through lysosomal pathways, preventing excessive activation of the signaling pathway. Furthermore, Cbls deficiency results in increased proliferation and decreased Apoptosis of macrophages in vitro and in vivo and dKO mice spontaneously develop a macrophage-dominated pulmonary enlargement. Together, these data demonstrate that Cbls play critical roles in the regulation of macrophage homeostasis by inhibiting M-CSFR-mediated Akt and ERK activation.

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