Esterase D stabilizes FKBP25 to suppress mTORC1

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• Esterase D (ESD) is an enzyme involved in formaldehyde detoxification.
• ESD's role in physiological and pathological processes is recognized, but its signaling pathway is not well understood.

Purpose of the Study:

• To investigate the molecular mechanism of Esterase D (ESD).
• To identify proteins interacting with ESD and elucidate its signaling pathway.
• To evaluate the effect of an ESD activator (FPD5) on cancer cell viability.

Main Methods:

• Yeast two-hybrid assay and co-immunoprecipitation (CO-IP) to identify ESD interacting proteins.
• Western blot to analyze phosphorylation of mTORC1 pathway components.
• Sulforhodamine B (SRB) and chick chorioallantoic membrane (CAM) assays to assess cell viability.

Main Results:

• FK506 binding protein 25 (FKBP25) was identified as an interacting protein with ESD, with the N-terminus of FKBP25 being crucial for interaction.
• ESD reduces K48-linked poly-ubiquitination of FKBP25, leading to its stabilization.
• ESD suppresses mTORC1 activity and inhibits tumor cell growth in vitro and in vivo through autophagy.

Conclusions:

• The study elucidates a novel molecular mechanism involving ESD and FKBP25 ubiquitination.
• The ESD/FKBP25/mTORC1 signaling pathway regulates autophagy and inhibits cancer cell proliferation.
• These findings offer insights into targeting this pathway for cancer therapy.