Lsm11-KO Mouse

Lsm11, a component of the replication-dependent histone pre-mRNA-processing complex, is crucial for the 3' end processing of metazoan replication-dependent histone pre-mRNAs. U7 snRNP, which contains Lsm11 and Lsm10 (replacing SmD1 and SmD2 in the canonical heptameric Sm protein ring), is essential for this process. Lsm11 is also involved in pathways related to the assembly of U7 snRNP, as it tightly interacts with the methylosome composed of PRMT5, MEP50, and pICln, which methylates Lsm11 [2,3].

Mutations in Lsm11 have been associated with Aicardi-Goutières syndrome, a rare monogenic autoimmune disease. These mutations lead to misprocessing of canonical histone transcripts, disturbance of linker histone stoichiometry, and enhanced interferon signaling mediated by the cGAS-STING pathway in patient-derived fibroblasts [1]. In Drosophila, a mutation in Lsm11 that prevents the binding of FLASH (a processing factor that binds Lsm11) cannot rescue the lethality or histone pre-mRNA processing defects resulting from an Lsm11 null mutation, demonstrating the essential role of the dFLASH-dLsm11 interaction for histone pre-mRNA processing in vivo and proper development in flies [4].

In conclusion, Lsm11 is essential for histone pre-mRNA processing and plays a significant role in development. Its malfunction due to mutations is associated with Aicardi-Goutières syndrome. Studies in model organisms like Drosophila have revealed its key interactions and functions, providing insights into the biological processes it is involved in and the disease mechanisms related to its dysfunction.

References:

1. Uggenti, Carolina, Lepelley, Alice, Depp, Marine, Gilbert, Nick, Crow, Yanick J. 2020. cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing. In Nature genetics, 52, 1364-1372. doi:10.1038/s41588-020-00737-3. https://pubmed.ncbi.nlm.nih.gov/33230297/

2. Yang, Xiao-Cui, Desotell, Anthony, Lin, Min-Han, Tong, Liang, Dominski, Zbigniew. 2023. In vitro methylation of the U7 snRNP subunits Lsm11 and SmE by the PRMT5/MEP50/pICln methylosome. In RNA (New York, N.Y.), 29, 1673-1690. doi:10.1261/rna.079709.123. https://pubmed.ncbi.nlm.nih.gov/37562960/

3. Yang, Xiao-Cui, Desotell, Anthony, Lin, Min-Han, Tong, Liang, Dominski, Zbigniew. 2023. In vitro methylation of the U7 snRNP subunits Lsm11 and SmE by the PRMT5/MEP50/pICln methylosome. In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.05.10.540203. https://pubmed.ncbi.nlm.nih.gov/37215023/

4. Burch, Brandon D, Godfrey, Ashley C, Gasdaska, Pamela Y, Marzluff, William F, Dominski, Zbigniew. 2011. Interaction between FLASH and Lsm11 is essential for histone pre-mRNA processing in vivo in Drosophila. In RNA (New York, N.Y.), 17, 1132-47. doi:10.1261/rna.2566811. https://pubmed.ncbi.nlm.nih.gov/21525146/