Shisa9, initially named CKAMP44, is an auxiliary subunit of the AMPA-type glutamate receptors and an autophagy cargo receptor. As an AMPA receptor auxiliary subunit, it modulates the physiological properties of these receptors, which are essential for neurotransmission in the central nervous system. As an autophagy cargo receptor, it is involved in the autophagy-dependent degradation process, thus playing a role in maintaining balanced autophagy, a crucial factor for brain integrity [2,3,4,1]. It has been associated with pathways related to immune responses in the central nervous system, as well as those regulating synaptic function [1,2,3]. Genetic models, such as knockout mouse models, can be valuable for studying Shisa9's functions.

In Shisa9-/-mice, they are highly susceptible to herpes simplex virus encephalitis. These mice also have pathogenic astrocytes and display more severe neuroinflammation compared with wild-type mice. This indicates that Shisa9 plays a critical role in modulating virus-induced neuroinflammation, likely through its function as an autophagy receptor that mediates the degradation of IKKi during herpes simplex virus type 1 infection [1].

In conclusion, Shisa9 is essential for both synaptic function as an AMPA receptor auxiliary subunit and for modulating neuroinflammation as an autophagy cargo receptor. The study of Shisa9 knockout mouse models has provided important insights into its role in herpes simplex virus-induced neuroinflammation, highlighting its potential significance in understanding and treating related central nervous system diseases.

References:

1. Zheng, Yanyan, Wang, Liqiu, Liu, Qingxiang, Jin, Shouheng, Cui, Jun. 2023. Modulation of virus-induced neuroinflammation by the autophagy receptor SHISA9 in mice. In Nature microbiology, 8, 958-972. doi:10.1038/s41564-023-01357-3. https://pubmed.ncbi.nlm.nih.gov/37081201/

2. Karataeva, Anna R, Klaassen, Remco V, Ströder, Jasper, Mansvelder, Huibert D, Smit, August B. 2014. C-terminal interactors of the AMPA receptor auxiliary subunit Shisa9. In PloS one, 9, e87360. doi:10.1371/journal.pone.0087360. https://pubmed.ncbi.nlm.nih.gov/24498314/

3. Kunde, Stella-Amrei, Rademacher, Nils, Zieger, Hanna, Shoichet, Sarah A. 2017. Protein kinase C regulates AMPA receptor auxiliary protein Shisa9/CKAMP44 through interactions with neuronal scaffold PICK1. In FEBS open bio, 7, 1234-1245. doi:10.1002/2211-5463.12261. https://pubmed.ncbi.nlm.nih.gov/28904854/

4. von Engelhardt, Jakob. 2019. AMPA Receptor Auxiliary Proteins of the CKAMP Family. In International journal of molecular sciences, 20, . doi:10.3390/ijms20061460. https://pubmed.ncbi.nlm.nih.gov/30909450/