DOI: 10.1681/asn.0000001169 ISSN: 1046-6673
Alanyl-tRNA Synthetase 1 and Cyst Growth in Autosomal Dominant Polycystic Kidney Disease
Lei Tian, Yumeng Wang, Linda Xiaoyan Li, Ewud Agborbesong, Julie Xia Zhou, Shan Mou, Xiaogang Li
Background:
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder, characterized by metabolic reprogramming with enhanced glycolysis and lactate accumulation. However, the enzyme that senses lactate and uses it as a substrate for protein lactylation in ADPKD remains unknown. Alanyl-tRNA synthetase 1 (AARS1) is a lactate-responsive enzyme with lactyltransferase activity, while its role and mechanisms in ADPKD have not been defined.
Methods:
To investigate the role of AARS1, we generated
Pkd1
and
Aars1
double conditional knockout
Pkd1
fl/fl
:Aars1
fl/fl
:Ksp-Cre
mice and evaluated the effect of AARS1 inhibitor, β-alanine, in two ADPKD mouse models. Coimmunoprecipitation and CUT&Tag analyses were performed to identify novel AARS1 substrates and downstream target genes involved in cystogenesis.
Results:
AARS1 was elevated in
Pkd1
mutant renal epithelial cells and kidneys, and genetic deletion of
Aars1
significantly delayed cyst growth, preserved kidney function, and reduced renal lactylation in
Pkd1
mutant mice. Mechanistically, AARS1 promoted lactylation-dependent activation of STAT3 and NF-κB (p65), specifically at STAT3 K140 and p65 K310, thereby amplifying pro-proliferative and pro-inflammatory transcriptional programs. AARS1 also associated with promoter regions and mediated histone H3K14 lactylation, thereby repressing the transcription of
Atg5
to impair autophagy and suppressing the transcription of
Dusp4
to sustain phosphorylation of cAMP response element–binding protein (CREB) and retinoblastoma protein (Rb). Cytokine signaling via IL-6 and TNF−α further reinforced AARS1 expression through STAT3- and NF-κB-dependent feed-forward loops. Importantly, inhibition of AARS1 with β-alanine markedly slowed cyst progression in
Pkd1
mutant mouse models.
Conclusions:
Our study identified AARS1 as a central metabolic sensor linking lactate-driven lysine lactylation to transcriptional, epigenetic, and signaling pathways that drive ADPKD progression.