Macrophage Ubiquitin-Activating Enzyme 1 Promotes Sepsis-Associated Acute Kidney Injury by Relieving Nucleoporin 35–Mediated Suppression of Nuclear Factor-κB Signaling

Abstract

Aims:

To determine the role of the ubiquitin-activating enzyme UBA1 in macrophage-mediated renal injury during sepsis-associated acute kidney injury (SA-AKI) and to elucidate the underlying molecular mechanism.

Methods and Results:

Using a cecal ligation and puncture mouse model, we evaluated renal function, inflammation, and survival in myeloid-specific Uba1 knockout mice (Uba1^M-KO) and littermate controls. Transcriptomic, proteomic, and ubiquitinome analyses were integrated with mechanistic studies in bone marrow–derived macrophages and renal tubular epithelial cell co-cultures. A pharmacologic UBA1 inhibitor (PYR-41) was tested for therapeutic efficacy. UBA1 expression was markedly increased in renal macrophages during SA-AKI. Uba1^M-KO mice demonstrated improved survival, preserved renal function, and attenuated inflammatory responses, as evidenced by reduced cytokine production, reactive oxygen species generation, apoptosis, and macrophage infiltration. Mechanistically, UBA1 promoted ubiquitination and degradation of the nuclear pore protein nucleoporin 35 (NUP35), impairing IκBα nuclear import and activating nuclear factor kappa B (NF-κB) signaling. This led to enhanced macrophage inflammatory activation and subsequent renal tubular injury. Pharmacologic inhibition of UBA1 recapitulated the protective effects of genetic deletion in vivo.

Innovation and Conclusions:

This study identifies UBA1-mediated NUP35 ubiquitination as a previously unrecognized checkpoint linking ubiquitin activation to nuclear pore integrity and inflammatory signaling in sepsis. UBA1 drives macrophage-mediated inflammation in SA-AKI by promoting NUP35 degradation and subsequent activation of NF-κB signaling. Targeting UBA1 represents a promising immunomodulatory strategy for the prevention and treatment of SA-AKI. Antioxid. Redox Signal. 44, 859–877.

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