Abstract: TH-PO0242
TRIM16 Facilitates Autophagy Activation and Renal Fibrosis by Promoting Ubiquitin-Mediated Degradation of S2448-Phosphorylated mTOR
Session Information
- CKD: Mechanisms of Injury and Fibrosis - 1
October 22, 2026 | Location: Exhibit Hall A, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2203 CKD (Non-Dialysis): Mechanisms
Authors
- Xie, Hongyan, Fudan University School of Basic Medical Sciences, Shanghai, China
- Xie, Jingyuan, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China
- Lu, Limin, Fudan University School of Basic Medical Sciences, Shanghai, China
Background
Chronic kidney disease (CKD) is a major public health concern, with renal fibrosis serving as a common pathological feature of progressive CKD. Autophagy plays a critical role in renal fibrosis, and targeted modulation of autophagic activity may help delay disease progression. The tripartite motif (TRIM) family comprises a large group of E3 ubiquitin ligases involved in autophagy regulation. However, the specific TRIM members and upstream regulatory mechanisms governing autophagy in renal fibrosis remain unclear.
Methods
Renal fibrosis was induced in mice by unilateral ureteral obstruction (UUO) or folic acid (FA) administration. Key TRIM family regulators were identified by overlapping autophagy-associated TRIM genes with differentially expressed TRIM genes from the UUO model. The mechanism of TRIM16 in autophagy regulation was investigated using immunoprecipitation-mass spectrometry, point mutation constructs, and ubiquitination assays. Tubular epithelial cell (TEC)-specific Trim16 knockout mice were employed to assess the role of TRIM16 in renal autophagy and fibrosis.
Results
Excessive autophagy activation accompanied by increased apoptosis was observed in both UUO- and FA-induced fibrotic kidneys. TRIM16, a key autophagy regulator, was upregulated in fibrotic kidneys. Elevated TRIM16 specifically promoted ubiquitination and degradation of the active form of mTOR (phosphorylated at Ser2448, p-mTOR) without altering total mTOR levels. Pharmacological activation of mTOR by MHY1485 or TEC-specific Trim16 knockout attenuated the reduction in mTOR activity, suppressed excessive autophagy and apoptosis, and mitigated renal fibrosis.
Conclusion
Elevated TRIM16 promotes ubiquitin-mediated degradation of the active form of mTOR (p-mTOR at Ser2448), leading to decreased mTOR activity, subsequent activation of autophagy, and ultimately contributing to renal fibrosis.
Funding
- Other NIH Support