Lnk deficiency enhances translesion synthesis to alleviate replication stress and promote hematopoietic stem cell fitness

Journal article

Tregs are critical for maintaining immune homeostasis, and their adoptive transfer can treat murine inflammatory disorders. In patients, Treg therapies have been variably efficacious. Therefore, new strategies to enhance Treg therapeutic efficacy are needed. Tregs predominantly depend on oxidative phosphorylation (OXPHOS) for energy and suppressive function. Fatty acid oxidation (FAO) contributes to Treg OXPHOS and can be important for Treg “effector” differentiation, but FAO activity is inhibited by coordinated activity of the isoenzymes acetyl-CoA carboxylase-1 and -2 (ACC1 and ACC2). Here, we show that small-molecule inhibition or Treg-specific genetic deletion of ACC1 significantly increases Treg suppressive function in vitro and in mice with established chronic graft-versus-host disease. ACC1 inhibition skewed Tregs toward an “effector” phenotype and enhanced FAO-mediated OXPHOS, mitochondrial function, and mitochondrial fusion. Inhibiting mitochondrial fusion diminished the effect of ACC1 inhibition. Reciprocally, promoting mitochondrial fusion, even in the absence of ACC1 modulation, resulted in a Treg functional and metabolic phenotype similar to that seen with ACC1 inhibition, indicating a key role for mitochondrial fusion in Treg-suppressive potency. Ex vivo–expanded, ACC1 inhibitor–treated human Tregs similarly augmented suppressor function, as observed with murine Tregs. Together, these data suggest that ACC1 manipulation may be exploited to modulate Treg function in patients.

Authors: McDonald-Hyman, C; Aguilar, EG; Compeer, EB; Zaiken, MC; Rhee, SY

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Society for Clinical Investigation
• Journal: The Journal of Clinical Investigation
• Volume: 136
• Issue: 1
• Pages: 1-21
• Publication date: 2025-10-30
• DOI: 10.1172/JCI191713
• EISSN: 1558-8238
• ISSN: 0021-9738
• Language: English
• Keywords: DNA repair; DNA synthesis; DNA polymerase; Haematopoiesis; Stem cell; DNA damage; DNA replication; Hematopoietic stem cell; Fanconi anemia