Investigations into the roles and molecular mechanisms of LanC-like proteins

Lanthionine;Akt;lanthionine synthetase C–like 2 (LanCL2)

Zeng, Min

关键词: Lanthionine;    Akt;    lanthionine synthetase C–like 2 (LanCL2);   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/78713/Zeng_Min.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Lanthipeptides are a family of ribosomally synthesized and posttranslationally modified natural products defined by the characteristic thioether crosslinks lanthionine and methyllanthionine. Among the various biological activities that lanthipeptides exhibit, the anti-microbial activities shown by many members of the family (hence named lantibiotics) have drawn the most attention and make them promising antibacterial drug candidates. One of the posttranslational modifications necessary for lanthipeptide synthesis and activity is a Michael-type addition of a cysteinyl thiol to dehydroalanine and dehydrobutyrine, catalyzed by the prokaryotic lantibiotic cyclase (LanC) or the cyclase domain in a multi-functional lantibiotic synthetase. Intriguingly, despite the lack of evidence of the presence of lanthipeptides in eukaryotes, sequence homologs of lantibiotic cyclases (LanC-like proteins or LanCL) have been found in a variety of eukaryotic species. The exploration of the biochemical and biological functions of LanC-like proteins may extend our understanding of the catalytic mechanisms of LanC or reveal novel modes of regulation of general interest. In this work, our understanding of the functions of mammalian LanC-like proteins has been broadened in different ways and novel mechanisms of action have been revealed. The characterization of LanCL2 function in mammalian cells is described in Chapter 2 and a novel function of LanCL2 as a regulator of Akt activity was identified. LanCL2 promotes Akt phosphorylation and cell survival in liver cells and this regulation is through directly facilitating Akt phosphorylation by mTORC2. Chapter 3 describes the establishment of LanCL knockout mouse lines and the phenotypic characterization of Lancl2-/- mice. Shortened life span was observed in Lancl2-/- mice, accompanied with the symptom of cardiomyopathy. These mice also showed increased susceptibility to microbial infections, which is suggestive of a compromised immune system. In Chapter 4, the role of LanCL proteins in lanthionine ketimine biosynthesis was investigated. The detection of lanthionine ketimine in LanCL triple knockout mice argues against an essential role of LanCL proteins in this pathway and suggests the need for a systematic screening for potential LanCL substrates. Lastly, Appendices A and B describes a functional study of LanCL2 in HEK293 and MCF-7 cells and the identification of novel LanCL2 interacting proteins, respectively.