Pacsin1-KO Mouse

Pacsin1, short for Protein Kinase C and Casein Kinase Substrate in Neurons 1, is a conserved peripheral membrane protein. It is involved in multiple cellular processes such as vesicle formation and transport, autophagy, and immune regulation [2,5]. In the context of autophagy, it is crucial for amphisome-lysosome fusion under basal nutrient-rich conditions, and for specific subsets of selective autophagy like lysophagy and aggrephagy [2]. In the immune system, it plays roles in regulating the TLR7/9-mediated type I interferon response in plasmacytoid dendritic cells [3].

In gastric cancer, Pacsin1 functions as an oncogene. Its deficiency inhibits autophagy but increases antigen presentation in GC cells. It also inhibits the lysosomal fusion and selective autophagy of MHC-I, leading to increased CD8 + T-cell infiltration and suppressed tumor growth and liver metastasis in vivo. Additionally, Pacsin1 knockout enhances the chemosensitivity of cells to immune checkpoint blockade [1]. In plasmacytoid dendritic cells, knockdown of Pacsin1 in human cell lines and knockout in mice reduces the type I IFN response to TLR9 ligand and virus, respectively [3]. A de novo missense variant (Q59K) in Pacsin1 in a child with SLE was found to increase IFNβ activity through impairment of TRAF4-mediated inhibition of TLR-7 signaling, possibly contributing to SLE risk [4]. In miiuy croaker, overexpression of pacsin1 promotes autophagic degradation of MITA, suppressing the innate antiviral response [5].

In conclusion, Pacsin1 is essential for autophagy-related fusion processes and immune-related signaling pathways. Studies using gene knockout models in mice and other loss-of-function experiments have revealed its role in diseases like gastric cancer, SLE, and antiviral immune responses in fish. These findings contribute to understanding the underlying mechanisms of these diseases and may potentially lead to new therapeutic strategies.

References:

1. Liu, Zhu, Li, Xin, Muhammad, Ali, Ren, Jun, Wang, Daorong. . PACSIN1 promotes immunosuppression in gastric cancer by degrading MHC-I. In Acta biochimica et biophysica Sinica, 56, 1473-1482. doi:10.3724/abbs.2024059. https://pubmed.ncbi.nlm.nih.gov/38826133/

2. Oe, Yukako, Kakuda, Keita, Yoshimura, Shin-Ichiro, Yoshimori, Tamotsu, Nakamura, Shuhei. 2022. PACSIN1 is indispensable for amphisome-lysosome fusion during basal autophagy and subsets of selective autophagy. In PLoS genetics, 18, e1010264. doi:10.1371/journal.pgen.1010264. https://pubmed.ncbi.nlm.nih.gov/35771772/

3. Esashi, Eiji, Bao, Musheng, Wang, Yi-Hong, Cao, Wei, Liu, Yong-Jun. . PACSIN1 regulates the TLR7/9-mediated type I interferon response in plasmacytoid dendritic cells. In European journal of immunology, 42, 573-9. doi:10.1002/eji.201142045. https://pubmed.ncbi.nlm.nih.gov/22488361/

4. Xie, Chengmei, Zhou, Haibo, Athanasopoulos, Vicki, He, Yuke, Vinuesa, Carola G. 2023. De Novo PACSIN1 Gene Variant Found in Childhood Lupus and a Role for PACSIN1/TRAF4 Complex in Toll-like Receptor 7 Activation. In Arthritis & rheumatology (Hoboken, N.J.), 75, 1058-1071. doi:10.1002/art.42416. https://pubmed.ncbi.nlm.nih.gov/36622335/

5. Li, Wenxin, Dong, Wenjing, Zhu, Zhihuang, Xu, Tianjun, Sun, Yuena. 2025. pacsin1 inhibits antiviral immunity by promoting MITA degradation through autophagy in miiuy croaker, Miichthysmiiuy. In Fish & shellfish immunology, 159, 110182. doi:10.1016/j.fsi.2025.110182. https://pubmed.ncbi.nlm.nih.gov/39923887/