Cover Story：Based on the powerful secondary metabolism of Streptomyces, they have been used to synthesize many biologically active secondary metabolites, such as antibiotics, anti-tumor drugs and immunosuppressants. Due to the fact that the synthesis of these products is often strictly regulated at multiple levels, therefore, the study of the mechanism of secondary metabolism regulation of Streptomyces can not only deepen our understanding of the metabolic regulation network of Streptomyces, but also provide important reference and guidance for the construction of industrial producing strains from the perspective of metabolism. There are two key types of signal transduction system in Streptomyces: two-component system (TCS) and extracytoplasmic function σ (ECF- σ). Both of them play important regulatory functions in the process of antibiotic biosynthesis. Studies have shown that there are a large number of TCS and ECF-σ coding genes in the genome of Streptomyces coelicolor, a model Streptomyces strain. In our previous studies, we have showed that, under certain conditions, the sigQ-afsQs gene cluster in S. coelicolor is involved in the regulation of the biosynthesis of ACT (actinorhodin), RED (undecylprodigiosin) and CDA (calcium-dependent antibiotic) antibiotics. Based on the early stage research on the regulation function of the TCS system afsQ1/Q2, a detailed study of the upstream regulation mechanism toward afsQ1/Q2 was carried out in this work. Through gene function verification experiments, it was found that the loss of sigQ can significantly down-regulate the expression of the membrane protein gene afsQ4 in the sigQafsQs gene cluster, and at the same time complementation afsQ4 can restore the phenotype of the sigQ deletion mutant (Δ sigQ), which indicates that afsQ4 is the downstream regulatory target of sigQ. Further analysis of in vitro phosphorylation experiments showed that the phosphorylation level of the transmembrane kinase AfsQ2 of TCS was significantly reduced in afsQ4 gene deletion mutant, indicating that sigQ can negatively regulate the TCS afsQ1/Q2 through membrane protein AfsQ4, and finally coordinate antibiotic synthesis.