Metabolic orchestration of NOD1 signaling by AMPK-mediated phosphorylation of ZDHHC5
Shaojie Mi, Yue Zhu, Qian Li, Wanjun Zhang, Huadong Pei, Feng Yao, Xuewu Guo, Yali Chen
TL;DR
This study shows how energy stress affects immune signaling by linking AMPK activity to NOD1 regulation through ZDHHC5.
Contribution
The paper reveals a new regulatory circuit where AMPK controls NOD1 signaling via phosphorylation of ZDHHC5.
Findings
AMPK phosphorylates ZDHHC5, reducing its membrane localization and NOD1 signaling.
NOD1 activation suppresses AMPK to maintain ZDHHC5 activity and immune response.
Metabolic stress coordinates immune signaling through AMPK and ZDHHC5 interactions.
Abstract
Innate immune responses must be coordinated with the cellular metabolic state. The intracellular pattern recognition receptor NOD1 detects bacterial peptidoglycans and initiates signaling from cellular membranes, a process regulated by ZDHHC5-mediated palmitoylation. Using biochemical analyses and immune-competent cell models, we show that AMP-activated protein kinase (AMPK) integrates metabolic cues into NOD1 signaling by regulating ZDHHC5. AMPK phosphorylates ZDHHC5 at Ser296 and Ser380, weakens its association with Golga7B, and promotes its displacement from the plasma membrane, thereby reducing NOD1 palmitoylation, membrane localization, and downstream signaling. Conversely, stimulation with the NOD1 agonist C12-iE-DAP suppresses AMPK activity, stabilizing ZDHHC5 at the membrane and sustaining NOD1 activation. These findings define a reciprocal regulatory circuit linking metabolic…
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Taxonomy
TopicsCancer, Hypoxia, and Metabolism · Metabolism, Diabetes, and Cancer · Mitochondrial Function and Pathology