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High hydrostatic pressure (HHP) is a characteristic environmental factor of the deep ocean. However, it remains unclear how piezotolerant bacteria adapt to HHP. Here, we identify a two-step metabolic pathway to cope with HHP stress in a piezotolerant bacterium. Myroides profundi D25 T , obtained from a deep-sea sediment, can take up trimethylamine (TMA) through a previously unidentified TMA transporter, TmaT, and oxidize intracellular TMA into trimethylamine N -oxide (TMAO) by a TMA monooxygenase, Mp Tmm. The produced TMAO is accumulated in the cell, functioning as a piezolyte, improving both growth and survival at HHP. The function of the TmaT- Mp Tmm pathway was further confirmed by introducing it into Escherichia coli and Bacillus subtilis Encoded TmaT-like and Mp Tmm-like sequences extensively exist in marine metagenomes, and other marine Bacteroidetes bacteria containing genes encoding TmaT-like and Mp Tmm-like proteins also have improved HHP tolerance in the presence of TMA, implying the universality of this HHP tolerance strategy in marine Bacteroidetes.

Oxidation of trimethylamine to trimethylamineN-oxide facilitates high hydrostatic pressure tolerance in a generalist bacterial lineage