Klhl22, an adaptor of the Cul3-based E3 ligase, is involved in multiple biological processes. It is associated with pathways such as the mTORC1 signaling pathway, which is a master regulator of cell growth responding to environmental cues like amino acids. KLHL22 also plays a role in maintaining PD-1 homeostasis in T cells, and is implicated in cancer-related pathways like the PI3K/Akt/mTOR and Wnt/β-catenin signaling pathways [1,2,3,4].

In mammals and nematodes, depletion of Klhl22 (or its orthologue MEL-26 in Caenorhabditis elegans) has significant effects. In C. elegans, depletion of MEL-26 extends lifespan [1]. In breast cancer cells, depletion of KLHL22 suppresses tumor growth in nude mice [1]. In colorectal cancer cells, KLHL22 expression is weaker in cancer tissues, and its overexpression inhibits cell invasion, migration, and proliferation in vitro and in vivo, potentially through the Wnt/β-catenin signaling pathway [4]. In melanoma cells, knockdown of KLHL22 suppresses cell proliferation both in vitro and in vivo by inactivating the PI3K/Akt/mTOR signaling pathway [3]. In T cells, KLHL22 deficiency leads to over-accumulation of PD-1, repressing the antitumor response and promoting tumor progression [2]. In a mouse model with conditional deletion of UBE4B in the nervous system, up-regulation of KLHL22 due to loss of UBE4B (which normally polyubiquitylates and degrades KLHL22) causes hyperactivation of mTOR, resulting in defective proliferation and differentiation of neural precursor cells, and suppression of KLHL22 expression can reverse this mTOR elevation [5].

In conclusion, Klhl22 is crucial in regulating mTORC1 signaling, PD-1 homeostasis, and cancer-related cellular processes. Gene-knockout or conditional-knockout models, especially in mice, have revealed its role in promoting tumorigenesis in breast and melanoma cancers, and in influencing lifespan in nematodes. These models also show its importance in maintaining proper neural development through fine-tuning of mTOR activity, highlighting its significance in understanding and potentially treating age-related and cancer-related diseases.

References:

1. Chen, Jie, Ou, Yuhui, Yang, Yanyan, Xie, Yuntao, Liu, Ying. 2018. KLHL22 activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing. In Nature, 557, 585-589. doi:10.1038/s41586-018-0128-9. https://pubmed.ncbi.nlm.nih.gov/29769719/

2. Zhou, Xiao Albert, Zhou, Jiadong, Zhao, Long, Wang, Wei, Wang, Jiadong. 2020. KLHL22 maintains PD-1 homeostasis and prevents excessive T cell suppression. In Proceedings of the National Academy of Sciences of the United States of America, 117, 28239-28250. doi:10.1073/pnas.2004570117. https://pubmed.ncbi.nlm.nih.gov/33109719/

3. Liu, X R, Wang, W, Li, H M. 2020. KLHL22 promotes malignant melanoma growth in vitro and in vivo by activating the PI3K/Akt/mTOR signaling pathway. In Neoplasma, 67, 1106-1113. doi:10.4149/neo_2020_190923N954. https://pubmed.ncbi.nlm.nih.gov/32484697/

4. Song, Yi, Yuan, Huiping, Wang, Jia, Xiao, Yuhong, Mao, Shengxun. 2020. KLHL22 Regulates the EMT and Proliferation in Colorectal Cancer Cells in Part via the Wnt/β-Catenin Signaling Pathway. In Cancer management and research, 12, 3981-3993. doi:10.2147/CMAR.S252232. https://pubmed.ncbi.nlm.nih.gov/32547233/

5. Kong, Xiangxing, Shu, Xin, Wang, Jiachuan, Guo, Xing, Wang, Zhiping. 2022. Fine-tuning of mTOR signaling by the UBE4B-KLHL22 E3 ubiquitin ligase cascade in brain development. In Development (Cambridge, England), 149, . doi:10.1242/dev.201286. https://pubmed.ncbi.nlm.nih.gov/36440598/