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Mammalian lipid droplets are innate immune hubs integrating cell metabolism and host defense

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Cells drop a bomb on pathogens

Lipid droplets (LDs) accumulate in cells to serve as lipid storage organelles. They are also an attractive source of nutrients for many pathogens. Bosch et al. show that various proteins involved in innate immunity form complexes on LDs in response to bacterial lipopolysaccharide (see the Perspective by Green). Upon activation, LDs became physically uncoupled from mitochondria, driving a shift in cells from oxidative phosphorylation to aerobic glycolysis. This work highlights the ability of LDs both to kill pathogens directly and to establish a metabolic environment conducive to host defense. This may inform future antimicrobial strategies in the age of antibiotic resistance.

Science, this issue p. eaay8085; see also p. 294

Structured Abstract

INTRODUCTION

In all eukaryotic cells, lipid droplets (LDs) store and supply essential lipids to produce signaling molecules, membrane building blocks, and metabolic energy. The LD monolayer also accommodates proteins not obviously related to lipids, such as transcription factors, chromatin components, and toxic proteins.

Common parasites (such as trypanosomes and Plasmodium falciparum), bacteria (such as mycobacteria and Chlamydia), and viruses (such as hepatitis C and dengue) induce and target LDs during their life cycles. The current view is that LDs support infection, providing microorganisms with substrates for effective growth.

RATIONALE

Successful innate defense is critical for survival, and host species have efficiently coevolved with pathogens to develop a plethora of immune responses. Multiple cues, including cellular stress and danger-associated molecular patterns such as lipopolysaccharide (LPS), induce LD formation. Thus, LD localization and dynamics may potentially be advantageous for organizing an intracellular host defense. We have investigated the possibility that mammalian LDs have a direct and regulated role in innate immunity.

RESULTS

We show that mammalian LDs are endowed with a protein-mediated antimicrobial capacity, which is up-regulated during polymicrobial sepsis and by LPS. Light and electron microscopy demonstrated specific association of LDs and bacteria in human macrophages, suggesting the existence of docking mechanisms that facilitate the engagement of antibacterial LD proteins with bacteria.

A comparative mass spectrometry profiling of proteins differentially associated with LDs in response to LPS (LPS-LDs) revealed the profound remodeling of the organelle proteome. A stringent evaluation identified 689 proteins differentially regulated on LPS-LDs (317 enriched and 372 reduced). Ingenuity Pathway Analysis revealed an enrichment of innate immune system–related components and reduction of metabolism-related LD-resident proteins. Additional analyses suggested that LDs serve as innate immune hubs, integrating major intra- and extracellular immune responses.

Among the five members of the perilipin family of LD surface proteins (PLINs), PLIN5 was the only one down-regulated on LPS-LDs. PLIN5 reduction promoted physical and functional disconnection of LPS-LDs and mitochondria, with a concomitant reduction of oxidative metabolism and ketogenesis. Forced PLIN5 reexpression increased the number of LD-mitochondria contacts, reducing LD-bacteria interactions and compromising the antimicrobial capacity of cells.

By contrast, PLIN2 was the most up-regulated PLIN on LPS-LDs. Gene interaction analysis revealed that multiple immune proteins nucleated around PLIN2 in response to LPS. LPS-LDs accrued several interferon-inducible proteins such as viperin, IGTP, IIGP1, TGTP1, and IFI47. Furthermore, LPS-LDs also accumulated cathelicidin (CAMP), a broad-spectrum antimicrobial peptide with chemotactic properties. Cells overexpressing a LD-associated CAMP were more resistant to different bacterial species, including Escherichia coli, methicillin-resistant Staphylococcus aureus, and Listeria monocytogenes.

CONCLUSION

These results demonstrate that LDs form a first-line intracellular defense. They act as a molecular switch in innate immunity, responding to danger signals by both reprogramming cell metabolism and eliciting protein-mediated antimicrobial mechanisms. Mechanisms of LD trafficking and docking with phagocytic and parasitophorous membranes, observed here and described for several pathogens, may facilitate the delivery of immune proteins located on the LD surface. Intracellular LDs can provide infected cells with several biological benefits, serving as a location to attract pathogens as well as coordinating different immune systems that operate simultaneously against different classes of pathogens. LDs may also sequester cytotoxic compounds (such as antimicrobial peptides), reducing damage to other cellular organelles. In view of the widespread resistance to current antibiotics, this study helps decipher molecular mechanisms involved in antimicrobial defense that could be exploited for development of new anti-infective agents.

LDs mediate innate immune defense.

Serial blockface scanning electron microscopy data reconstruction showing an infected macrophage. Bacteria (blue) and LDs (green) in the three-dimensional dataset have been colored and projected onto a single image. LDs associate with the bacteria surface (black square). This interaction is proposed to bring a specific set of antipathogenic proteins in contact with the membrane-enclosing bacteria (inset).

Abstract

Lipid droplets (LDs) are the major lipid storage organelles of eukaryotic cells and a source of nutrients for intracellular pathogens. We demonstrate that mammalian LDs are endowed with a protein-mediated antimicrobial capacity, which is up-regulated by danger signals. In response to lipopolysaccharide (LPS), multiple host defense proteins, including interferon-inducible guanosine triphosphatases and the antimicrobial cathelicidin, assemble into complex clusters on LDs. LPS additionally promotes the physical and functional uncoupling of LDs from mitochondria, reducing fatty acid metabolism while increasing LD-bacterial contacts. Thus, LDs actively participate in mammalian innate immunity at two levels: They are both cell-autonomous organelles that organize and use immune proteins to kill intracellular pathogens as well as central players in the local and systemic metabolic adaptation to infection.

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Science

Too bright to breed

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Night light from coastal cities overpowers natural signals for coral spawning from neighboring reefs.

PHOTO: NOKURO/ALAMY STOCK PHOTO

Most coral species reproduce through broadcast spawning. For such a strategy to be successful, coordination has had to evolve such that gametes across clones are released simultaneously. Over millennia, lunar cycles have facilitated this coordination, but the recent development of bright artificial light has led to an overpowering of these natural signals. Ayalon et al. tested for the direct impact of different kinds of artificial light on different species of corals. The authors found that multiple lighting types, including cold and warm light-emitting diode (LED) lamps, led to loss of synchrony and spawning failure. Further, coastal maps of artificial lighting globally suggest that it threatens to interfere with coral reproduction worldwide and that the deployment of LED lights, the blue light of which penetrates deeper into the water column, is likely to make the situation even worse.

Curr. Biol. 10.1016/j.cub.2020.10.039 (2020).

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SpaceX launches Starlink app and provides pricing and service info to early beta testers

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SpaceX has debuted an official app for its Starlink satellite broadband internet service, for both iOS and Android devices. The Starlink app allows users to manage their connection – but to take part you’ll have to be part of the official beta program, and the initial public rollout of that is only just about to begin, according to emails SpaceX sent to potential beta testers this week.

The Starlink app provides guidance on how to install the Starlink receiver dish, as well as connection status (including signal quality), a device overview for seeing what’s connected to your network, and a speed test tool. It’s similar to other mobile apps for managing home wifi connections and routers. Meanwhile, the emails to potential testers that CNBC obtained detail what users can expect in terms of pricing, speeds and latency.

The initial Starlink public beta test is called the “Better than Nothing Beta Program,” SpaceX confirms in their app description, and will be rolled out across the U.S. and Canada before the end of the year – which matches up with earlier stated timelines. As per the name, SpaceX is hoping to set expectations for early customers, with speeds users can expect ranging from between 50Mb/s to 150Mb/s, and latency of 20ms to 40ms according to the customer emails, with some periods including no connectivity at all. Even with expectations set low, if those values prove accurate, it should be a big improvement for users in some hard-to-reach areas where service is currently costly, unreliable and operating at roughly dial-up equivalent speeds.

Image Credits: SpaceX

In terms of pricing, SpaceX says in the emails that the cost for participants in this beta program will be $99 per moth, plus a one-time cost of $499 initially to pay for the hardware, which includes the mounting kit and receiver dish, as well as a router with wifi networking capabilities.

The goal eventually is offer reliably, low-latency broadband that provides consistent connection by handing off connectivity between a large constellation of small satellites circling the globe in low Earth orbit. Already, SpaceX has nearly 1,000 of those launched, but it hopes to launch many thousands more before it reaches global coverage and offers general availability of its services.

SpaceX has already announced some initial commercial partnerships and pilot programs for Starlink, too, including a team-up with Microsoft to connect that company’s mobile Azure data centers, and a project with an East Texas school board to connect the local community.

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Erratum for the Report “Meta-analysis reveals declines in terrestrial but increases in freshwater insect abundances” by R. Van Klink, D. E. Bowler, K. B. Gongalsky, A. B. Swengel, A. Gentile, J. M. Chase

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S. Rennie, J. Adamson, R. Anderson, C. Andrews, J. Bater, N. Bayfield, K. Beaton, D. Beaumont, S. Benham, V. Bowmaker, C. Britt, R. Brooker, D. Brooks, J. Brunt, G. Common, R. Cooper, S. Corbett, N. Critchley, P. Dennis, J. Dick, B. Dodd, N. Dodd, N. Donovan, J. Easter, M. Flexen, A. Gardiner, D. Hamilton, P. Hargreaves, M. Hatton-Ellis, M. Howe, J. Kahl, M. Lane, S. Langan, D. Lloyd, B. McCarney, Y. McElarney, C. McKenna, S. McMillan, F. Milne, L. Milne, M. Morecroft, M. Murphy, A. Nelson, H. Nicholson, D. Pallett, D. Parry, I. Pearce, G. Pozsgai, A. Riley, R. Rose, S. Schafer, T. Scott, L. Sherrin, C. Shortall, R. Smith, P. Smith, R. Tait, C. Taylor, M. Taylor, M. Thurlow, A. Turner, K. Tyson, H. Watson, M. Whittaker, I. Woiwod, C. Wood, UK Environmental Change Network (ECN) Moth Data: 1992-2015, NERC Environmental Information Data Centre (2018); .

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