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The Hippo signaling component LATS2 enhances innate immunity to inhibit HIV-1 infection through PQBP1-cGAS pathway

Abstract

As the most primordial signaling pathway in animal physiology, the Hippo pathway and innate immunity play crucial roles not only in sensing cellular conditions or infections, but also in various metabolite homeostasis and tumorigenesis. However, the correlation between cellular homeostasis and antiviral defense is not well understood. The core kinase LATS1/2, could either enhance or inhibit the anti-tumor immunity in different cellular contexts. In this study, we found that LATS2 can interact with PQBP1, the co-factor of cGAS, thus enhanced the cGAS-STING mediated innate immune response to HIV-1 challenge. LATS2 was observed to upregulate type-I interferon (IFN-I) and cytokines in response to HIV-1 reverse-transcribed DNA and inhibited HIV-1 infection. Due to the involvement of PQBP1, the function of LATS2 in regulating cGAS activity is not relying on the downstream YAP/TAZ as that in the canonical Hippo pathway. The related kinase activity of LATS2 was verified, and the potential phosphorylation site of PQBP1 was identified. Our study established a novel connection between Hippo signaling and innate immunity, thus may provide new potential intervention target on antiviral therapeutics.

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Fig. 1: Identification of LATS2 as a PQBP1-associated protein.
Fig. 2: LATS2 inhibits HIV-1 infection.
Fig. 3: LATS2 upregulates the cellular innate immune response upon HIV-1 infection.
Fig. 4: LATS2 regulates antiviral signaling at the upstream of STING.
Fig. 5: LATS2 functions dependently on its kinase activity.
Fig. 6: The influence of LATS2 on cGAS is mediated by PQBP1.
Fig. 7: LATS2 is essential for HIV-1-induced oligomerization of cGAS.

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Acknowledgements

We thank Dr. David Levy (University of Alabama at Birmingham), Dr. Wentao Qiao (Nankai University), and Dr. Min Wei (Nankai University) for providing retrovirus plasmids. We also thank Dr. Youjia Cao (Nankai University) for providing HSV-1. This project is supported by the National Natural Science Foundation of China (31870730, 31671513, and 82002136).

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SW and XL conceived the project. TSH and XL designed the experiments. TSH, LD, JZ, JZ, GW, and EW performed the experiments. HX provided essential materials. TSH and XL analyzed the data and wrote the paper. WZ, SW, and XL revised the manuscript.

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Correspondence to Shian Wu or Xinqi Liu.

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He, TS., Dang, L., Zhang, J. et al. The Hippo signaling component LATS2 enhances innate immunity to inhibit HIV-1 infection through PQBP1-cGAS pathway. Cell Death Differ 29, 192–205 (2022). https://doi.org/10.1038/s41418-021-00849-1

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