Heat stress-induced degradation of glutamine synthetase rebalances central carbon-nitrogen metabolism and promotes thermotolerance in Ganoderma lucidum

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ABSTRACT Thermotolerance is fundamental to fungal ecology and survival. Although heat stress triggers extensive metabolic reprogramming, the function of these changes for thermotolerance has remained poorly understood. Here, we identify glutamine synthetase (GS), a central nitrogen metabolism enzyme, as a critical determinant of thermotolerance in Ganoderma lucidum . Silencing of gs significantly enhanced fungal tolerance under heat stress and reduced the relative inhibition rate of mycelial growth to 9.71%, compared with 20.7% in the wild-type (WT) strain. Heat stress also increased reactive oxygen species and H ₂ O ₂ levels by 1.49- and 1.38-fold in the WT strain, whereas the increments were markedly lower in gs -silenced strains. Subsequently, under heat stress, α-ketoglutarate contents in WT increased by 1.49-fold. Inhibition of GS further increased the accumulation, which was achieved by upregulating glutamate dehydrogenase to promote the conversion of glutamate to α-ketoglutarate. This metabolic response was correlated with the generation of adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NADH). Moreover, under heat stress, the level of GS protein in WT strains decreased by 29.0%, compared with that under normal conditions, due to accelerated degradation via the 26S proteasome. Our findings reveal that a ubiquitin-dependent signal instantaneously rebalances central carbon-nitrogen metabolism, offering a direct and rapid link between central metabolism and thermotolerance in fungi. IMPORTANCE Understanding how organisms adapt to heat stress is of increasing urgency in the context of global warming. While the roles of heat-shock proteins and antioxidant systems are well established, how microbes actively reprogram central metabolism to survive thermal challenge remains a fundamental, unanswered question. This study reveals that the central nitrogen metabolism enzyme glutamine synthetase (GS) is degraded by the ubiquitin-proteasome system and that this degradation acts as a metabolic switch to enhance thermotolerance in Ganoderma lucidum . We discovered that heat stress induces ubiquitin-proteasome system-dependent GS degradation, leading to redirected central nitrogen flux that elevates α-ketoglutarate content. This metabolic shift boosts ATP and NADH production. In summary, our findings represent a significant advance beyond classical protein chaperone systems and reactive oxygen species-scavenging systems, highlighting a direct and rapid link between metabolic flux and thermotolerance.

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