Abstract
The biogenesis of membrane proteins requires assistance from a YidC/Oxa1/Alb3 family protein. To maintain the cellular capacity of this process, Bacillus subtilis, a gram-positive bacterium, adopts a unique feedback mechanism, in which dysfunction of the primary YidC paralogue, SpoIIIJ (YidC1), induces the synthesis of the secondary paralogue, YidC2 (YqjG). MifM (membrane insertion and folding monitor), a ribosome arrest polypeptide, is a key component of this unique regulatory mechanism. Although MifM itself is inserted into the membrane by the YidC system, it contains an amino acid sequence that interacts uniquely with the B. subtilis ribosome and induces its stalling. Ribosome stalling on mifM-yidC2 mRNA, which is prolonged in response to the dysfunction of SpoIIIJ, unfolds a secondary structure of the mRNA, thereby exposing the Shine–Dalgarno (SD) sequence of yidC2 and allowing its translation initiation. The arrest is regulated such that it is released when the nascent MifM polypeptide undergoes SpoIIIJ-mediated membrane insertion. MifM is unique in that it stalls the ribosome at multiple consecutive codons rather than at a single site. This chapter highlights the unique mechanism and regulation of elongation arrest revealed for MifM.
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Acknowledgments
I wish to express my gratitude to several individuals who guided the course of my research, ultimately leading to the fascinating world of MifM analysis. When I was a Ph.D. student in Koreaki Ito’s laboratory in Kyoto University, Hitoshi Nakatogawa, my peer at the time and one of my best friends, was also working in the lab as a Ph.D. student. He began the characterization of SecM (it was originally called “gene X”) and soon discovered its elongation arrest. In those days, I was studying the membrane protein degradation in Escherichia coli and was not directly involved in ribosome arrest peptides. Nonetheless, these exciting years with Hitoshi, Koreaki, and the other Ito lab members were a crucial and formative period of my development. After 2 years of postdoctoral experience in the same lab, I began my second postdoctoral research experience (2004–2008) in the laboratory of Kit Pogliano at UCSD, where I first became interested in investigating the membrane protein dynamics that Bacillus subtilis undergoes during sporulation. Meanwhile, Aileen Rubio and Xin Jiang, other post-docs in the Pogliano lab and also my good friends, had found that, in B. subtilis, yidC2 was induced in response to dysfunction of SpoIIIJ (YidC1); their work on this subject was published in 2005. In my last year in San Diego, Aileen and Xin had already left the laboratory and there seemed to be no further interest in the project of YidC2 regulation. I eventually asked Kit if I could work on this topic. It was too intriguing for me to ignore. Kit encouraged me to pursue this project, especially because we were already aware of an intriguing similarity between the YidC2 regulation in B. subtilis and the SecM system in E. coli (in part through my own work back in Kyoto). Indeed, she was so generous as to offer me continued pursuit of this project, presuming it went well, as a building block in my own career. Anne Lamsa, a graduate student of the Pogliano lab, also joined this project. Bioinformatics was not useful to identify arrest peptides because they could be highly divergent and the ribosome-profiling technique was not yet readily available. Fortunately, my encounter with SecM and MifM happened in the right places and in the right chronological order to allow me to proceed along a productive path using ordinary biochemical and genetic approaches to solve what MifM was doing. After coming back to Japan, I joined Yoshinori Akiyama’s lab at Kyoto University for 2 years. Yoshinori generously allowed me to continue my MifM research in his lab while I assisted in his research on the proteolysis of membrane proteins. In 2010, when Koreaki, after retirement from Kyoto University, accepted a professorship at Kyoto Sangyo University, I was appointed an assistant professor at this university, where we started a unique collaboration. Now the investigation of SecM and MifM, the two known arrest peptides that sense and control protein trafficking in the cell, is merged. This happy collaboration continues at this moment. With this unusually long introduction, I thank all my previous and current friends, collaborators, and mentors for having guided me to the exciting world of regulatory nascent chains in general and to MifM in particular, and for their great encouragement and support. Special thanks are due to Professor Koreaki Ito for providing me this great opportunity to write a chapter of this book and also for his careful editing and advice during the manuscript preparation.
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Chiba, S. (2014). MifM, a Regulatory Nascent Chain That Monitors Membrane Protein Integration. In: Ito, K. (eds) Regulatory Nascent Polypeptides. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55052-5_15
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