Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a spectrum of heterogeneous diseases characterized by osteoarticular and dermatological manifestations. Osteitis and hyperostosis are core clinical manifestations in SAPHO syndrome, typically affecting multiple areas and possibly progressing to irreversible osteoarticular damage. Most patients with SAPHO have cutaneous involvement, mainly manifested as palmoplantar pustulosis and severe acne. Systemic manifestations are uncommon but occasionally reported. Epidemiological studies suggest the annual prevalence of SAPHO syndrome varies from 0.00144 in 100,000 in Japanese individuals to fewer than 1 in 10,000 in White individuals. The precise etiopathogenesis of SAPHO remains unclear, but it is generally considered an autoinflammatory syndrome that may be related to various etiologies, such as immune dysfunction, infection and genetic predisposition. Owing to the relapsing–remitting disease course, the goal of management is to improve clinical symptoms and prevent disease progression. Various treatments, including nonsteroidal anti-inflammatory drugs, conventional disease-modifying antirheumatic drugs, bisphosphonates, biologics, and antibiotics, are promising options for alleviating the disease.
How the plasma membrane senses external heat-stress signals to communicate with chloroplasts to orchestrate thermotolerance remains elusive. We identified a quantitative trait locus, Thermo-tolerance 3 ( TT3 ), consisting of two genes, TT3.1 and TT3.2 , that interact together to enhance rice thermotolerance and reduce grain-yield losses caused by heat stress. Upon heat stress, plasma membrane–localized E3 ligase TT3.1 translocates to the endosomes, on which TT3.1 ubiquitinates chloroplast precursor protein TT3.2 for vacuolar degradation, implying that TT3.1 might serve as a potential thermosensor. Lesser accumulated, mature TT3.2 proteins in chloroplasts are essential for protecting thylakoids from heat stress. Our findings not only reveal a TT3.1-TT3.2 genetic module at one locus that transduces heat signals from plasma membrane to chloroplasts but also provide the strategy for breeding highly thermotolerant crops.
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