2. Academic Validation
  3. HSPA8 dampens SCAP/INSIG split and SREBP activation by reducing PKR-mediated INSIG phosphorylation

HSPA8 dampens SCAP/INSIG split and SREBP activation by reducing PKR-mediated INSIG phosphorylation

  • Cell Rep. 2025 Mar 25;44(3):115339. doi: 10.1016/j.celrep.2025.115339.
Guangyan Yang 1,  Chuanrui Ma 2,  Yuanli Chen 3,  Jiaqing Xiang 4,  Lixing Li 4,  Yanchun Li 4,  Lin Kang 5,  Zhen Liang 6,  Shu Yang 7
Affiliations

Affiliations

  • 1 Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People's Hospital), Shenzhen, Guangdong 518020, China; Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China; Shantou University Medical College, Shantou, Guangdong, China.
  • 2 First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China.
  • 3 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Anhui Provincial International Science and Technology Cooperation Base for Major Metabolic Diseases and Nutritional Interventions, School of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
  • 4 Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People's Hospital), Shenzhen, Guangdong 518020, China; Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China.
  • 5 Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People's Hospital), Shenzhen, Guangdong 518020, China; Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China. Electronic address: kang.lin@szhospital.com.
  • 6 Department of Geriatrics, Peking University Shenzhen Hospital, Shenzhen, China; Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China. Electronic address: liang.zhen@szhospital.com.
  • 7 Department of Geriatrics, The First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People's Hospital), Shenzhen, Guangdong 518020, China; Guangdong Provincial Clinical Research Center for Geriatrics, Shenzhen Clinical Research Center for Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China. Electronic address: yang.shu@szhospital.com.
PMID: 39977267 DOI: 10.1016/j.celrep.2025.115339
Abstract

Lipid accumulation in renal tubules is a major determinant of diabetic kidney disease (DKD), and activation of SREBPs plays a central role in this process. Our study aims to explore whether HSPA8, a molecular chaperone, is the master regulator of INSIG/SREBPs function in DKD. Here, we show that tubular epithelial cell (TEC)-specific knockout of HSPA8 upregulates the phosphorylation of INSIG1 and INSIG2, which disrupts the interaction between INSIG proteins and SCAP, leading to SREBP activation. TEC-specific overexpression of HSPA8 restrains these changes. INSIG1/2 can be phosphorylated by protein kinase R (PKR), while HSPA8 recognizes PKR and recruits the E3 ubiquitin Ligase to promote PKR ubiquitination and degradation. Under temporary hyperglycemic stimulation, SREBP1 transcriptionally activates HSPA8 expression. Conversely, persistent hyperglycemia reduces HSPA8 levels via promoting NF-κB-mediated transcriptional inhibition of HSPA8. Collectively, these findings indicate that the molecular chaperone HSPA8 serves as a negative feedback regulator of SREBPs, lipogenesis, and DKD development.

Keywords

CP: Metabolism; CP: Molecular biology; Diabetic kidney disease; HSPA8; INSIGs; PKR; SREBPs; lipid accumulation.

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