Klhl42, also known as Kelch-like protein 42, is an E3 ubiquitin ligase. E3 ubiquitin ligases play a crucial role in the ubiquitin-proteasome system, which is responsible for regulating protein turnover in cells. They target specific proteins for ubiquitination and subsequent degradation by the proteasome, thus regulating various biological processes [2].

In cancer, MYC amplification can confer resistance to CDK4/6 inhibitors in bladder, prostate, and breast cancer cells. MYC binds to the promoter of KLHL42, enhancing its transcription. KLHL42 then induces both phosphorylated and total pRB1 ubiquitination and degradation, leading to RB1 deficiency and resistance to CDK4/6i [1].

In systemic sclerosis, knockdown of KLHL42 in primary SSc patient lung cells impairs TGF-β-dependent profibrotic signaling, reduces fibrotic tissue production, and decreases TGF-β-mediated SMAD activation. PPP2R5ϵ was identified as a KLHL42 substrate, and its knockdown exacerbated TGF-β-mediated profibrotic signaling, indicating the role of the KLHL42-PPP2R5ϵ axis in controlling profibrotic signaling in SSc lung fibroblasts [3].

In cutaneous T cell lymphoma, KLHL42 was transcriptionally activated by GATA3 in Sézary syndrome (SS). Silencing KLHL42 significantly inhibited aggressive CTCL cell proliferation and promoted apoptosis, suggesting targeting KLHL42 as a potential therapeutic approach [4].

In conclusion, Klhl42 is an important E3 ubiquitin ligase involved in cancer drug resistance, fibrotic diseases, and cutaneous T cell lymphoma. Research on Klhl42 using loss-of-function models such as knockdown in patient cells has provided insights into its role in these disease-related biological processes, potentially paving the way for new therapeutic strategies in these disease areas.

References:

1. Ma, Jian, Li, Lei, Ma, Bohan, Wei, Wenyi, Li, Lei. 2024. MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation. In Nature communications, 15, 1871. doi:10.1038/s41467-024-45796-w. https://pubmed.ncbi.nlm.nih.gov/38424044/

2. Shen, Wanlu, Zhang, Zhigang, Ma, Jiaqing, Lu, Di, Lyu, Lechun. 2021. The Ubiquitin Proteasome System and Skin Fibrosis. In Molecular diagnosis & therapy, 25, 29-40. doi:10.1007/s40291-020-00509-z. https://pubmed.ncbi.nlm.nih.gov/33433895/

3. Lear, Travis B, Lockwood, Karina C, Larsen, Mads, Liu, Yuan, Chen, Bill B. 2020. Kelch-like protein 42 is a profibrotic ubiquitin E3 ligase involved in systemic sclerosis. In The Journal of biological chemistry, 295, 4171-4180. doi:10.1074/jbc.AC119.012066. https://pubmed.ncbi.nlm.nih.gov/32071084/

4. Xue, Xiaotong, Wang, Zhenzhen, Mi, Zihao, Liu, Hong, Zhang, Furen. 2022. Single-cell analyses reveal novel molecular signatures and pathogenesis in cutaneous T cell lymphoma. In Cell death & disease, 13, 970. doi:10.1038/s41419-022-05323-5. https://pubmed.ncbi.nlm.nih.gov/36400759/