Tollip, short for Toll-interacting protein, is an inhibitory adaptor protein. It is involved in multiple innate immune signaling pathways such as TLR2, TLR4, IL-1R, and STING [5]. It also plays a role in endosomal trafficking and acts as a key regulator in maintaining cellular homeostasis, with its functions spanning from innate immunity modulation to autophagy-related processes. Genetic models, like KO mouse models, have been crucial in understanding its functions.

In Tollip -/- mice, TB severity is increased, characterized by macrophage-and T cell-driven inflammation, foam cell formation, and lipid accumulation. Tollip -/- alveolar macrophages specifically accumulate lipid, undergo necrosis, and show increased EIF2 signaling and upregulation of the integrated stress response (ISR) upon Mycobacterium tuberculosis infection [1]. In the context of alpha-herpesvirus, the tegument protein UL21 triggers CGAS degradation through TOLLIP-mediated selective autophagy, dampening type I interferon signaling [2]. In triple-negative breast cancer, TMEM63A is stabilized by VCP through blocking its TOLLIP-mediated autophagic degradation, promoting cancer progression [3]. For SARS-CoV-2, TOLLIP-dependent autophagic degradation of ACE2 is affected by its SUMOylation, with TOLLIP deficiency leading to elevated virus infection [4].

In conclusion, Tollip is essential in modulating innate immunity, autophagy, and cellular stress responses. The study of Tollip -/- mouse models has provided insights into its role in diseases such as tuberculosis, viral infections, and cancer. Understanding Tollip's functions can potentially lead to the development of new therapeutic strategies for these diseases.

References:

1. Venkatasubramanian, Sambasivan, Plumlee, Courtney R, Dill-McFarland, Kimberly A, Urdahl, Kevin B, Shah, Javeed A. 2024. TOLLIP inhibits lipid accumulation and the integrated stress response in alveolar macrophages to control Mycobacterium tuberculosis infection. In Nature microbiology, 9, 949-963. doi:10.1038/s41564-024-01641-w. https://pubmed.ncbi.nlm.nih.gov/38528148/

2. Ma, Zicheng, Bai, Juan, Jiang, Chenlong, Jiang, Ping, Liu, Xing. 2022. Tegument protein UL21 of alpha-herpesvirus inhibits the innate immunity by triggering CGAS degradation through TOLLIP-mediated selective autophagy. In Autophagy, 19, 1512-1532. doi:10.1080/15548627.2022.2139921. https://pubmed.ncbi.nlm.nih.gov/36343628/

3. Zhang, Tai-Mei, Liao, Li, Yang, Shao-Ying, Shao, Zhi-Min, Li, Da-Qiang. 2022. TOLLIP-mediated autophagic degradation pathway links the VCP-TMEM63A-DERL1 signaling axis to triple-negative breast cancer progression. In Autophagy, 19, 805-821. doi:10.1080/15548627.2022.2103992. https://pubmed.ncbi.nlm.nih.gov/35920704/

4. Jin, Shouheng, He, Xing, Ma, Ling, Zhao, Jincun, Cui, Jun. 2022. Suppression of ACE2 SUMOylation protects against SARS-CoV-2 infection through TOLLIP-mediated selective autophagy. In Nature communications, 13, 5204. doi:10.1038/s41467-022-32957-y. https://pubmed.ncbi.nlm.nih.gov/36057605/

5. Venkatasubramanian, Sambasivan, Pryor, Robyn, Plumlee, Courtney, Urdahl, Kevin B, Shah, Javeed A. 2022. TOLLIP Optimizes Dendritic Cell Maturation to Lipopolysaccharide and Mycobacterium tuberculosis. In Journal of immunology (Baltimore, Md. : 1950), 209, 435-445. doi:10.4049/jimmunol.2200030. https://pubmed.ncbi.nlm.nih.gov/35803695/