Innate immune and proinflammatory signals activate the Hippo pathway via a Tak1-STRIPAK-Tao axis

• Published in: Nature communications 2024-01, Vol.15 (1), p.145-17, Article 145
• Main Authors: Yang, Yinan, Zhou, Huijing, Huang, Xiawei, Wu, Chengfang, Zheng, Kewei, Deng, Jingrong, Zheng, Yonggang, Wang, Jiahui, Chi, Xiaofeng, Ma, Xianjue, Pan, Huimin, Shen, Rui, Pan, Duojia, Liu, Bo
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/31; 13/89; 14/19; 14/5; 38/77; 631/136/334/1582/715; 631/250/2502; 631/250/262/2106; 631/80/86; 82/29; 96/95; Cell death; Cell growth; Gram-positive bacteria; Hippo Signaling Pathway; Humanities and Social Sciences; Immunity, Innate; Immunological memory; Insects; Kinases; Life sciences; Lysosomes; Mammalian cells; multidisciplinary; Pathogens; Phagocytosis; Phosphatase; Phosphorylation; Protein Serine-Threonine Kinases - metabolism; Proteins; Science; Science (multidisciplinary); Signal Transduction; Stimuli; TAK1 protein; Tumor necrosis factor-TNF
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-44542-y

The Hippo pathway controls developmental, homeostatic and regenerative tissue growth, and is frequently dysregulated in various diseases. Although this pathway can be activated by innate immune/inflammatory stimuli, the underlying mechanism is not fully understood. Here, we identify a conserved signaling cascade that leads to Hippo pathway activation by innate immune/inflammatory signals. We show that Tak1, a key kinase in innate immune/inflammatory signaling, activates the Hippo pathway by inducing the lysosomal degradation of Cka, an essential subunit of the STRIPAK PP2A complex that suppresses Hippo signaling. Suppression of STRIPAK results in the activation of Hippo pathway through Tao-Hpo signaling. We further show that Tak1-mediated Hippo signaling is involved in processes ranging from cell death to phagocytosis and innate immune memory. Our findings thus reveal a molecular connection between innate immune/inflammatory signaling and the evolutionally conserved Hippo pathway, thus contributing to our understanding of infectious, inflammatory and malignant diseases. The evolutionally conserved Hippo pathway regulates essential developmental, homeostatic and regenerative processes, and is involved in the host defense against pathogens. Here authors show that in Drosophila Melanogaster and mammalian cells, innate immune stimuli activate Hippo via a pathway emanating from the Tak1 kinase and cascading down to Hippo via STRIPAK-Tao-Hpo signaling.