Visualizing suborganellar lipid distribution using correlative light and electron microscopy - Nature Cell Biology Lennartz et al. introduce a correlative light and electron microscopy workflow, Lipid-CLEM, combining near-native lipid probes and on-section labelling via click chemistry. Lipid-CLEM quantitatively a...

I am extremely excited that my first first-author paper from my PhD is finally out 😆!! We developed a new CLEM workflow to measure lipid densities at the nanoscale. So if you are into lipids and super-resolution imaging approaches, this one is for you: www.nature.com/articles/s41...

Congratulations!!

Excited to share our new paper and lipid- and protein-directed photocatalytic labeling method (POCA) just out in @natchembio.nature.com. tinyurl.com/2kcxuvvv. Big congrats to first author Andrew Becker and the whole team for launching our lab into the wild world of singlet oxygen interactomics.

Congratulations - well deserved!

Membrane editing with proximity labeling reveals regulators of lipid homeostasis - Nature Chemical Biology Coupling an optogenetic lipid-modifying enzyme with proximity labeling reveals protein networks and mechanisms regulating lipid homeostasis in the membranes of target organelles.

Thrilled to share our latest study, led by @reikatei.bsky.social, in @natchembio.nature.com! We began by asking a simple question—how do cells know if they have too much of a lipid in a particular membrane, and how do they respond to rectify this imbalance?
www.nature.com/articles/s41...
More info 👇

To all lipid-curious cell biologists: check out this comprehensive overview of lipid-based methods by @gerryhammond.bsky.social and colleagues in @jcb.org — a school of Babel fish for #lipidtime:

rupress.org/jcb/article/...

Profiling the proteome-wide selectivity of diverse electrophiles - Nature Chemistry Covalent inhibitors are powerful entities in drug discovery. Now the amino acid selectivity and reactivity of a diverse electrophile library have been assessed proteome-wide using an unbiased workflow...

How can we study target engagement and selectivity of covalent inhibitors? Which electrophilic probes are best suited to study a certain amino acid?

Our study on "Profiling the proteome-wide selectivity of diverse electrophiles" is published in Nature Chemistry.(1/7)

www.nature.com/articles/s41...

The Division of Chemistry and Chemical Engineering at Caltech invites applications for a faculty position at all levels and in all areas of chemistry, biochemistry, and chemical engineering.

Interested candidates should apply at
applications.caltech.edu/job/chemistry

Deadline: Dec. 1, 2025.

Discovery, Optimization, and Anticancer Activity of Lipid-Competitive Pleckstrin Homology Domain-Containing Family A Inhibitors Phosphoinositide signaling is a major cellular mechanism controlling cancer cell viability, proliferation, and survival. Yet, inhibition of lipid kinases that produce oncogenic phosphoinositides has afforded only a limited number of efficacious drugs attributed in large part to on-target toxicity resulting from the pleiotropic effects of these signaling lipids. Targeting the specific phosphoinositide effector pathways via competitive inhibitors of phosphoinositide-recognizing pleckstrin homology (PH) domains represents a relatively unexplored means to achieve greater specificity. Herein, we present the discovery from in silico screening, structure–activity relationship (SAR) optimization, and cellular characterization of novel phosphoinositide-competitive inhibitors of the pleckstrin homology domain-containing A (PLEKHA) family. These compounds induce cytotoxic effects in BRAF and NRAS mutant melanoma cells, consistent with on-target inhibition, and the most potent compound is activated by endogenous esterase activity, suggesting that prodrug esters represent a viable strategy for targeting the phosphoinositide-binding pockets of the PLEKHA family of PH domains.

A while back we found that the lipid-binding protein PLEKHA4 boosts Wnt/β-catenin signaling and drives melanoma growth in vivo. Now, we (Nathan Frederick) identify small-molecule inhibitors of PLEKHA4 & related proteins with anticancer activity in vitro! pubs.acs.org/doi/10.1021/....

Out today in @nature.com: Together with the Honigmann, Shevchenko, Drobot and Hof labs, we present a general workflow for imaging the localization and transport of individual lipids in cells and mapping their metabolism.
www.nature.com/articles/s41...

Thank you Jeremy!

Quantitative imaging of lipid transport in mammalian cells - Nature Directional, non-vesicular lipid transport is responsible for fast, species-selective lipid sorting into organelle membranes.

Quite a week for #lipidtime: phenomenal study using bifunctional lipid probes to quantify intracellular lipid transport from @nadlerlab.bsky.social and colleagues is now out @nature.com! www.nature.com/articles/s41...

Organelle-Targeted Laurdans Measure Heterogeneity in Subcellular Membranes and Their Responses to Saturated Lipid Stress Organelles feature characteristic lipid compositions that lead to differences in membrane properties. In cells, membrane ordering and fluidity are commonly measured using the solvatochromic dye Laurdan, whose fluorescence is sensitive to lipid packing. As a general lipophilic dye, Laurdan stains all hydrophobic environments in cells; therefore, it is challenging to characterize membrane properties in specific organelles or assess their responses to pharmacological treatments in intact cells. Here, we describe the synthesis and application of Laurdan-derived probes that read out the membrane packing of individual cellular organelles. The set of organelle-targeted Laurdans (OTL) localizes to the ER, mitochondria, lysosomes, and Golgi compartments with high specificity while retaining the spectral resolution needed to detect biological changes in membrane ordering. We show that ratiometric imaging with OTLs can resolve membrane heterogeneity within organelles as well as changes in lipid packing resulting from inhibition of trafficking or bioenergetic processes. We apply these probes to characterize organelle-specific responses to saturated lipid stress. While the ER and lysosomal membrane fluidity is sensitive to exogenous saturated fatty acids, that of mitochondrial membranes is protected. We then use differences in ER membrane fluidity to sort populations of cells based on their fatty acid diet, highlighting the ability of organelle-localized solvatochromic probes to distinguish between cells based on their metabolic state. These results expand the repertoire of targeted membrane probes and demonstrate their application in interrogating lipid dysregulation.

The 4 chemically targeted Laurdan derivatives (for mitochondria, ER, lyso/endosomes, and the Golgi) that we published last year are now available (at a pretty reasonable price) from Avanti Polar Lipids (cat #880194, 880197, 880193, 880196). These have been very popular! pubs.acs.org/doi/full/10....

@harayamajrlab.bsky.social @reynders.bsky.social @acs.org @acsbiol.bsky.social @caltechcce.bsky.social @pennchemistry.bsky.social #lipidtime #chembio #molswitch #chemsky

Optical Control of Membrane Viscosity Modulates ER-to-Golgi Trafficking The lipid composition of cellular membranes is highly dynamic and undergoes continuous remodeling, affecting the biophysical properties critical to biological function. Here, we introduce an optical a...

Excited to share our new @pubs.acs.org paper! We engineered cells with ~10% photolipids in the ER membrane. This enabled optical control of membrane viscosity to study its impact on ER→Golgi protein transport. @dirktrauner.bsky.social @noemijimenezrojo.bsky.social

pubs.acs.org/doi/10.1021/...

Thrilled to have our story on the regulation of lysosomal lipids out in @cp-cellmetabolism.bsky.social! The work was led by two outstanding grad students Jess Davidson and Raghav Jain probing mechanistic control of energy expenditure @hhmi.org @uwbiochem.bsky.social

Why are biological membranes asymmetric, with different lipids in the two bilayer leaflets? Discovered in the 70s, lipid asymmetry is linked to many cellular processes, but why the cell needs it is largely unclear. @pavelbarahtjan.bsky.social addresses this question: www.biorxiv.org/content/10.1...

Engineered Proteins and Chemical Tools to Probe the Cell Surface Proteome The cell surface proteome, or surfaceome, is the hub for cells to interact and communicate with the outside world. Many disease-associated changes are hard-wired within the surfaceome, yet approved drugs target less than 50 cell surface proteins. In the past decade, the proteomics community has made significant strides in developing new technologies tailored for studying the surfaceome in all its complexity. In this review, we first dive into the unique characteristics and functions of the surfaceome, emphasizing the necessity for specialized labeling, enrichment, and proteomic approaches. An overview of surfaceomics methods is provided, detailing techniques to measure changes in protein expression and how this leads to novel target discovery. Next, we highlight advances in proximity labeling proteomics (PLP), showcasing how various enzymatic and photoaffinity proximity labeling techniques can map protein–protein interactions and membrane protein complexes on the cell surface. We then review the role of extracellular post-translational modifications, focusing on cell surface glycosylation, proteolytic remodeling, and the secretome. Finally, we discuss methods for identifying tumor-specific peptide MHC complexes and how they have shaped therapeutic development. This emerging field of neo-protein epitopes is constantly evolving, where targets are identified at the proteome level and encompass defined disease-associated PTMs, complexes, and dysregulated cellular and tissue locations. Given the functional importance of the surfaceome for biology and therapy, we view surfaceomics as a critical piece of this quest for neo-epitope target discovery.

Excited to share that our cell surface proteome review is now online on Chemical Reviews! 🥰 We highlight recent advances of techniques mapping cell surface protein expression, protein-protein interactions, extracellular PTMs and MHC complexes. @jimwellsucsf.bsky.social pubs.acs.org/doi/10.1021/...

Congratulations on the Eli Lilly Award Brian!

Great to see you Jeremy - congratulations on the ACS Chem Biol Young Investigator Award!!

Are lipids actively sorted during clathrin mediated endocytosis like proteins? @mathilda95.bsky.social addresses this key open question together with our collaborators from the Honigmann and Modes labs using a new Lipid-STED workflow.
www.biorxiv.org/content/10.1...

🚨New preprint: There's this overlooked phospholipid with 3 acyl tails called NAPE that is made during ischemia. We identified its interactome & found it regulates lactate flux, suggesting metabolic functions in response to hypoxia. Congrats to Dylan Chiu! doi.org/10.26434/che... #lipidtime #chembio

Yes for deep red I was thinking 640

For me this would probably cover 80-90% of my organelle staining dye needs - I wonder what other people doing live cell imaging think? Thanks for considering this Luke! Hoechst would also be great but I think it’s a bit more affordable.

ER and Mitochondria would be great! I think Lysosome and PM would also be very useful. With a suit of ER, Mito, Lyso, and PM in two colors e.g. green and deep red (8 dyes total) one could mix and match any and also have flexibility to pair with anything else in either green or red.

Thank you Luke! Organelle tracking dyes come to mind. Getting a full suit of them and different colors easily costs thousands $

Concise Synthesis of (−)-Veratramine and (−)-20-iso-Veratramine via Aromative Diels–Alder Reaction A concise and convergent synthesis of the isosteroidal alkaloids veratramine and 20-iso-veratramine has been accomplished. A Horner–Wadsworth–Emmons olefination joins two chiral building blocks of app...

Check out our paper on veratramine and isosteroidal alkaloids, now published in JACS.

pubs.acs.org/doi/10.1021/...

table of contents graphic for review titled synthetic lipid biology

abstract of review article

Po-Hsun Brian Chen

Xiang-Ling (Julia) Li

Overjoyed and honestly relieved to share a Chem Rev magnum opus from Brian Chen & Julia Li titled Synthetic Lipid Biology! In it, we organize efforts across numerous fields to create, manipulate, and analyze lipids and biomembranes. Check it out! doi.org/10.1021/acs.... #lipidtime #chemsky #chembio

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giving.caltech.edu/areas-to-sup...

Great study & very useful tool! Congrats Reika!