Magnesium homeostasis is essential for life and depends on magnesium transporters, whose activity and ion selectivity need to be tightly controlled. Rhomboid intramembrane proteases pervade the prokaryotic kingdom, but their functions are largely elusive. Using proteomics, we find that Bacillus subtilis rhomboid protease YqgP interacts with the membrane-bound ATP-dependent processive metalloprotease FtsH and cleaves MgtE, the major high-affinity magnesium transporter in B. subtilis. MgtE cleavage by YqgP is potentiated in conditions of low magnesium and high manganese or zinc, thereby protecting B. subtilis from Mn2+ /Zn2+ toxicity. The N-terminal cytosolic domain of YqgP binds Mn2+ and Zn2+ ions and facilitates MgtE cleavage. Independently of its intrinsic protease activity, YqgP acts as a substrate adaptor for FtsH, a function that is necessary for degradation of MgtE. YqgP thus unites protease and pseudoprotease function, hinting at the evolutionary origin of rhomboid pseudoproteases such as Derlins that are intimately involved in eukaryotic ER-associated degradation (ERAD). Conceptually, the YqgP-FtsH system we describe here is analogous to a primordial form of "ERAD" in bacteria and exemplifies an ancestral function of rhomboid-superfamily proteins.

CEA Inserm IRIG BGE Univ Grenoble Alpes Grenoble France

Institute of Organic Chemistry and Biochemistry Czech Academy of Science Prague Czech Republic

Institute of Organic Chemistry and Biochemistry Czech Academy of Science Prague Czech Republic Department of Biochemistry Faculty of Science Charles University Prague Czech Republic

Institute of Organic Chemistry and Biochemistry Czech Academy of Science Prague Czech Republic Department of Cell Biology Faculty of Science Charles University Prague Czech Republic

Institute of Organic Chemistry and Biochemistry Czech Academy of Science Prague Czech Republic Department of Genetics and Microbiology Faculty of Science Charles University Prague Czech Republic

Laboratoire de Chimie Bactérienne CNRS UMR 7255 Aix Marseille Univ Marseille Cedex 20 France

Laboratoire de Chimie Bactérienne CNRS UMR 7283 Aix Marseille Univ Marseille Cedex 20 France

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$a Began, Jakub $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Science, Prague, Czech Republic. Department of Genetics and Microbiology, Faculty of Science, Charles University, Prague, Czech Republic.

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$a Rhomboid intramembrane protease YqgP licenses bacterial membrane protein quality control as adaptor of FtsH AAA protease / $c J. Began, B. Cordier, J. Březinová, J. Delisle, R. Hexnerová, P. Srb, P. Rampírová, M. Kožíšek, M. Baudet, Y. Couté, A. Galinier, V. Veverka, T. Doan, K. Strisovsky,

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$a Magnesium homeostasis is essential for life and depends on magnesium transporters, whose activity and ion selectivity need to be tightly controlled. Rhomboid intramembrane proteases pervade the prokaryotic kingdom, but their functions are largely elusive. Using proteomics, we find that Bacillus subtilis rhomboid protease YqgP interacts with the membrane-bound ATP-dependent processive metalloprotease FtsH and cleaves MgtE, the major high-affinity magnesium transporter in B. subtilis. MgtE cleavage by YqgP is potentiated in conditions of low magnesium and high manganese or zinc, thereby protecting B. subtilis from Mn2+ /Zn2+ toxicity. The N-terminal cytosolic domain of YqgP binds Mn2+ and Zn2+ ions and facilitates MgtE cleavage. Independently of its intrinsic protease activity, YqgP acts as a substrate adaptor for FtsH, a function that is necessary for degradation of MgtE. YqgP thus unites protease and pseudoprotease function, hinting at the evolutionary origin of rhomboid pseudoproteases such as Derlins that are intimately involved in eukaryotic ER-associated degradation (ERAD). Conceptually, the YqgP-FtsH system we describe here is analogous to a primordial form of "ERAD" in bacteria and exemplifies an ancestral function of rhomboid-superfamily proteins.

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$a Cordier, Baptiste $u Laboratoire de Chimie Bactérienne (LCB), Institut de Microbiologie de la Méditerranée (IMM), CNRS, UMR 7283, Aix Marseille Univ, Marseille Cedex 20, France.

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$a Březinová, Jana $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Science, Prague, Czech Republic. Department of Biochemistry, Faculty of Science, Charles University, Prague, Czech Republic.

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$a Delisle, Jordan $u Laboratoire de Chimie Bactérienne (LCB), Institut de Microbiologie de la Méditerranée (IMM), CNRS, UMR 7283, Aix Marseille Univ, Marseille Cedex 20, France.

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$a Hexnerová, Rozálie $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Science, Prague, Czech Republic.

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$a Rampírová, Petra $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Science, Prague, Czech Republic.

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$a Kožíšek, Milan $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Science, Prague, Czech Republic.

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$a Baudet, Mathieu $u CEA, Inserm, IRIG-BGE, Univ. Grenoble Alpes, Grenoble, France.

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$a Galinier, Anne $u Laboratoire de Chimie Bactérienne (LCB), Institut de Microbiologie de la Méditerranée (IMM), CNRS, UMR 7283, Aix Marseille Univ, Marseille Cedex 20, France.

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$a Veverka, Václav, $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Science, Prague, Czech Republic. Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic. $d 1973- $7 xx0301322

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$a Doan, Thierry $u Laboratoire de Chimie Bactérienne (LCB), Institut de Microbiologie de la Méditerranée (IMM), CNRS, UMR 7283, Aix Marseille Univ, Marseille Cedex 20, France. Laboratoire d'Ingénierie des Systèmes Macromoléculaires (LISM), Institut de Microbiologie de la Méditerranée (IMM), CNRS, UMR 7255, Aix Marseille Univ, Marseille Cedex 20, France.

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$a Strisovsky, Kvido $u Institute of Organic Chemistry and Biochemistry, Czech Academy of Science, Prague, Czech Republic.

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