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bioRxiv · 10.1101/2022.12.21.521298

A Borrelia burgdorferi LptD Homolog Facilitates Flipping of Surface Lipoproteins Through the Spirochetal Outer Membrane

He, H.·Pramanik, A. S.·Swanson, S. K.·Johnson, D. K.·Florens, L.·Zueckert, W. R.
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Abstract

Borrelia spirochetes are unique among diderm bacteria in their lack of lipopolysaccharide (LPS) in the outer membrane (OM) and their abundance of surface-exposed lipoproteins with major roles in transmission, virulence, and pathogenesis. Despite their importance, little is known about how surface lipoproteins are translocated through the periplasm and the OM. In this study, we characterized Borrelia burgdorferi BB0838, a distant homolog of the OM LPS assembly protein LptD. Using a CRISPR interference approach, we showed that BB0838 is essential for cell growth. Upon BB0838 knockdown, sentinel surface lipoprotein OspA was retained in the inner leaflet of the OM, as determined by its inaccessibility to in situ proteolysis but its presence in OM vesicles. The secretion, insertion and topology of the B. burgdorferi OM porin P66 remained unaffected. MudPIT quantitative mass spectrometry analysis of the B. burgdorferi membrane-associated proteome further confirmed the selective periplasmic retention of surface lipoproteins under BB0838 knockdown conditions. Alphafold Multimer modeling predicted a B. burgdorferi LptB2FGCAD complex spanning the periplasm. Together, this indicates that BB0838 facilitates the essential terminal step in a distinctive spirochetal lipoprotein secretion pathway that evolved in parallel to the LPS secretion pathway in gram-negative bacteria. Hence, BB0838/LptDBb represents an attractive target for novel antimicrobials.

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He, H., Pramanik, A. S., Swanson, S. K., Johnson, D. K., Florens, L., Zueckert, W. R.. 2022-12-22. A Borrelia burgdorferi LptD Homolog Facilitates Flipping of Surface Lipoproteins Through the Spirochetal Outer Membrane. https://doi.org/10.1101/2022.12.21.521298

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