Hopanoids As Functional Analogues of Cholesterol in Bacterial Membranes

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Hopanoids As Functional Analogues of Cholesterol in Bacterial Membranes Hopanoids as functional analogues of cholesterol in bacterial membranes James P. Sáenza,1, Daniel Grossera, Alexander S. Bradleyb, Thibaut J. Lagnya, Oksana Lavrynenkoa, Martyna Brodaa,c, and Kai Simonsa,1 aMax Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany; bDepartment of Earth and Planetary Sciences, Washington University, St. Louis, MO 63130; and cDepartment of Biotechnology, University of Wroclaw, 50-383 Wroclaw, Poland Contributed by Kai Simons, August 18, 2015 (sent for review July 8, 2015; reviewed by Damien Devos and Felix Goni) The functionality of cellular membranes relies on the molecular order fluid but mechanically robust plasma membrane (12). Early invest- imparted by lipids. In eukaryotes, sterols such as cholesterol modulate igations showed that both sterols and hopanoids exhibit the ability membrane order, yet they are not typically found in prokaryotes. The to condense lipids (13, 14). We demonstrated that hopanoids are structurally similar bacterial hopanoids exhibit similar ordering prop- indeed bacterial sterol surrogates with respect to their ability to erties as sterols in vitro, but their exact physiological role in form a liquid ordered phase, and that they promote liquid-liquid living bacteria is relatively uncharted. We present evidence that phase separation in membranes (15). This observation decouples hopanoids interact with glycolipids in bacterial outer membranes to the evolution of ordered biochemically active liquid membranes form a highly ordered bilayer in a manner analogous to the interac- from the requirement for molecular oxygen and suggests that the tion of sterols with sphingolipids in eukaryotic plasma membranes. ability to subcompartmentalize membranes could have preceded Furthermore, multidrug transport is impaired in a hopanoid-deficient the evolution of sterols. Subsequently, it was shown that hopanoid- Methylobacterium extorquens mutant of the gram-negative ,which based ordering can be tuned by structural modifications of their introduces a link between membrane order and an energy-depen- ring structure or polar side chain (16, 17). dent, membrane-associated function in prokaryotes. Thus, we reveal It is clear that hopanoids in vitro exhibit an ability to order a convergence in the architecture of bacterial and eukaryotic mem- synthetic membranes in a sterol-like manner (15). However, it is branes and implicate the biosynthetic pathways of hopanoids and not known whether hopanoids impart molecular order within other order-modulating lipids as potential targets to fight patho- genic multidrug resistance. bacterial membranes in vivo, and with which lipids they interact to achieve such order. Hopanoids have been identified in many membrane order | hopanoids | multidrug efflux | outer membrane | gram-negative bacteria (18, 19), but their exact physiological role Methylobacterium is unclear. Deletion of hopanoid synthesis is nonlethal in the bacteria that have been studied so far, but hopanoid-deficient mutants have been shown to exhibit increased sensitivity to an- terols (e.g., cholesterol; Fig. S1) are ubiquitous eukaryotic tibiotics and detergents as well as susceptibility to stresses, in- Smembrane lipids with a planar geometry that endows them – with a propensity to constrain, and thereby order, lipid bilayers. cluding variation in pH, temperature, and osmotic pressure (20 The principal terms contributing to lipid order are the rotational 24). It is not understood precisely how hopanoids are linked to freedom of motion and lateral packing of the lipids within the antibiotic resistance and tolerance to stress, but understanding plane of the bilayer. Lipid order is directly linked to essential the role of hopanoids in shaping membrane properties would membrane properties, including fluidity, permeability, lateral provide an important step toward bridging this gap. segregation, and the propensity for membranes to bind and in- tegrate other biomolecules (1). High plasma membrane order is Significance a fundamental property shared across the domains of modern PHYSIOLOGY life, and it may have been a key factor in the selective fitness of The function of the cell membrane as a barrier and a matrix for primitive life (2). However, sterols as the primary membrane- biochemical activity relies on the properties imparted by lipids. ordering lipid present a conundrum because sterol biosynthesis In eukaryotes, sterols are crucial for modulating the molecular requires molecular oxygen, but life was present on Earth at least order of membranes. Sterol ordering provides the basis for a billion years before cyanobacteria first enriched the atmo- membrane lateral segregation and promotes a fluid, mechanically sphere with oxygen (3, 4). Are there lipids that could have pro- robust plasma membrane. How do organisms that lack sterols moted membrane ordering before sterol synthesis emerged? determine membrane order? Hopanoids are bacterial membrane All three domains of life share isoprenoid synthesis pathways lipids that have been demonstrated to have sterol-like properties that give rise to a broad suite of structurally homologous lipids, in vitro. We now explore the distribution of hopanoids and their including sterols and hopanoids (e.g., diplopterol; Fig. S1). Hopa- effect on membranes in Methylobacterium extorquens.Wefind noids are some of the most ubiquitous cyclic isoprenoidal lipids in that hopanoids determine bacterial outer membrane order in a the sedimentary record, and they have been used as molecular manner analogous to sterol ordering in the eukaryotic plasma proxies for ancient microbial life (5). Importantly, hopanoid syn- membrane, and that their deletion impairs energy-dependent thesis does not require molecular oxygen, and hopanoids have been multidrug efflux. reported in sediments predating the enrichment of oxygen in Earth’s atmosphere (6, 7). Their discovery led to the proposal Author contributions: J.P.S. and K.S. designed research; J.P.S., D.G., A.S.B., T.J.L., O.L., and M.B. performed research; A.S.B. and O.L. contributed new reagents/analytic tools; J.P.S. that they might serve as sterol surrogates in bacteria (8), espe- analyzed data; and J.P.S. wrote the paper. cially because hopanoids and sterols share common structural Reviewers: D.D., Uni. Pablo de Olavide, Sevilla, Spain; and F.G., Unidad de Biofisica features and are cyclized by closely related enzymes (9, 10). Leioa Spain. One of the properties of sterols in eukaryotes is their ability to The authors declare no conflict of interest. interact preferentially with lipids such as sphingomyelin (SM) to 1To whom correspondence may be addressed. Email: [email protected] or simons@mpi- form liquid ordered phases in lipid membranes (11). This inter- cbg.de. action provides the mechanistic basis for the underlying intercon- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. nectivity supporting membrane lateral segregation and promoting a 1073/pnas.1515607112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1515607112 PNAS | September 22, 2015 | vol. 112 | no. 38 | 11971–11976 Downloaded by guest on September 24, 2021 To understand how the ordering capacity of hopanoids con- Polar Apolar tributes to membrane functionality, it is necessary to examine IM OM IM OM membrane physiology in vivo. Here, we have explored the physi- ology of a hopanoid-producing organism from a physicochemical perspective by measuring the distribution of hopanoids and their effect on membranes in the gram-negative plant-associated bacte- rium Methylobacterium extorquens. We demonstrate that hopanoids preferentially interact with outer membrane (OM) glycolipids to Diplopterols produce highly ordered membranes, thus revealing a convergent strategy for the functional ordering of bacterial and eukaryotic Phospholipids surface membranes. We also identify impaired multidrug efflux as a phenotype of hopanoid deletion, which we propose accounts for sensitivity to chemical stresses. Our findings imply a link between membrane order and protein function in prokaryotes. They also suggest a possible lipid target to address bacterial multidrug re- sistance, further implicating isoprenoidal lipid biosynthesis as a bacterial Achilles heel (25, 26). hopanoids Polar Results and Discussion Fig. 1. Hopanoids are enriched in the OM. A TLC plate shows phospholipid Hopanoids Are Localized in the OM and Determine Membrane Order. and hopanoid distributions in OM and inner membrane (IM) fractions. The The major hopanoids in M. extorquens are diplopterol and its major hopanoids detected are diplopterols (diplopterol and 2-methyl-dip- methylated derivative 2-methyl-diplopterol (Fig. S1), which together lopterol; Fig. S1) and polar hopanoids (BHT-GCE and BHT-CE; Fig. S1). make up most of the total hopanoid content (27). M. extorquens also Structures were confirmed by MS. produces extended side-chain polar hopanoids, known as bacter- iohopanepolyols (BHPs), predominately composed of a bacter- conclude that hopanoids, as well as cholesterol itself, have the po- iohopanetetrol cyclitol ether (BHT-CE) and its guanidine-modified tential to determine order in the outer bacterial membrane. derivative (BHT-GCE) (28) (Fig. S1). Trace quantities (<1% of total hopanoid) of BHT and adenosylhopane can also be detected, Hopanoids Are Predicted to Interact Preferentially with Lipid A in the but these trace quantities are most likely just biosynthetic inter- OM. It remained unclear which lipids hopanoids interact with
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