Steven P. Gygi

A multivalent docking platform and Rcn1-mediated inhibition control the extent of calcineurin recruitment to the cell division site for the dephosphorylation of multiple cytokinetic proteins

Alaina H. Willet, Jun‐Song Chen, Qing Hua Yu, Chloe E. Snider et autres

Cytokinesis requires coordinated signaling to ensure the accurate physical separation of daughter cells. Calcineurin (CN), a conserved Ca 2+ /calmodulin-dependent phosphatase, is required for cytokinesis in organisms ranging from yeast to humans, yet how CN is regulated at the division site and …

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A sensitive method for profiling cell-type-specific secretomes of rare cells from complex tissues

Gergana Shipkovenska, Xuchao Lyu, Manalee Vishnu Surve, João A. Paulo et autres

Very rare cells often have outsized physiologic functions. However, their low abundance presents a technical challenge for studying their function. Here, we generate a murine model, which enables the profiling of secreted proteomes (secretomes) from physiologically relevant low-abundance cells in complex tissues, …

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Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of interorganellar lipid cycling

Юлия Караваева, Astrid Linde Basse, Samuel A.J. Trammell, Mohammed Faiz Hussain et autres

Abstract Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature. Yet how these diverse signals are molecularly integrated remains unknown. Here we show that clock, diet, and temperature cues converge on the orphan mitochondrial transporter, SLC25A34, to orchestrate thermogenic …

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A cyclin-polarity feedback network ensures healthy cell proliferation

Landry Peyran, Charles Lefranc, Steven P. Gygi, Anne Royou et autres

Abstract Healthy proliferation requires the coordination of cell cycle progression with cell polarity. In budding yeast, polarity is established when G1-cyclin-Cdc28Cdk1 triggers Cdc42 activation to generate a cell pole that is used as an axis for growth and division. While polarity defects …

Mitochondrial l-2-hydroxyglutarate is a physiological signalling metabolite

Ram P. Chakrabarty, Jonathan G. Van Vranken, Yuki Aoi, Taylor A. Poor et autres

l-2-Hydroxyglutarate (l-2-HG) is a low-abundance metabolite in mammals because the mitochondrial enzyme l-2-HG dehydrogenase (L2HGDH) oxidizes l-2-HG to 2-oxoglutarate (2-OG) to prevent its accumulation1. In humans, a lack of L2HGDH activity leads to l-2-HG accumulation and causes l-2-hydroxyglutaric aciduria2. Thus, l-2-HG is …

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Therapeutic remodeling of the ceramide backbone prevents kidney injury

Rebekah J. Nicholson, Luis Cedeño-Rosario, J. Alan Maschek, Jonathan G. Van Vranken et autres

Perturbation of proximal tubule (PT) lipid metabolism fuels the pathological features of acute kidney injury (AKI). We found that AKI induced biosynthesis of lipotoxic ceramides within PTs in humans and mice and that urine ceramides predicted disease severity in children and adults. …

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Ribosome remodeling drives translation adaptation during viral infection and cellular stress

Hsin-Yu Tsai, Luochen Liu, Julian Mintseris, Derrick Ekanayake et autres

The ribosome is the highly conserved molecular machine that decodes mRNAs during protein synthesis. While traditionally thought to consist of a uniform set of proteins, here we discover that ribosome composition is reprogrammed to adapt to intrinsic and external cellular perturbations. During …

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Catalytic pocket of Clr4 (Suv39h) methyltransferase serves as a substrate receptor for Cullin 4-dependent histone H3 ubiquitination

Katarína Pšenáková, Swapnil S. Parhad, João A. Paulo, Xinyue Liu et autres

Histone H3 lysine 9 (H3K9) methylation must be regulated to prevent inappropriate heterochromatin formation. Regulation of the conserved fission yeast H3K9 methyltransferase Clr4 (Suv39h) involves an automethylation-induced conformational switch and interaction of its catalytic SET domain with mono-ubiquitinated histone H3 lysine 14 …

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CRISPR screens and quantitative proteomics reveal remodeling of the aryl hydrocarbon receptor–driven proteome through PARP7 activity

Andrii Gorelik, João A. Paulo, Christina B. Schroeter, Melanie Lad et autres

to attach a single ADP-ribose moiety onto proteins related to immunity, transcription, and cell growth and motility. Despite the importance of PARP7 in these processes, PARP7 signaling networks remain underresearched. Here, we used genome-wide CRISPR screens and multiplex quantitative proteomics in distinct …

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Interrupting ELMSAN1 repression of nuclear acetyl-CoA production therapeutically reprograms cancer cells

Ting Zhao, Lingli He, Lai Ping Wong, Shenglin Mei et autres

SUMMARY Metabolites are essential substrates for epigenetic modifications. Although nuclear acetyl-CoA constitutes a small fraction of the whole cell pool, it regulates cell fate by locally providing histone acetylation substrate. Here, we combined phenotypic chemical screen and genome-wide CRISPR screen to demonstrate …

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TMT-Based Multiplexed (Chemo)Proteomics on the Orbitrap Astral Mass Spectrometer

Yuchen He, Ka Yang, Shaoxian Li, Martin Zeller et autres

Ongoing advancements in instrumentation has established mass spectrometry (MS) as an essential tool in proteomics research and drug discovery. The newly released Asymmetric Track Lossless (Astral) analyzer represents a major step forward in MS instrumentation. Here, we evaluate the Orbitrap Astral mass …

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Insights into the Absence of Lymphoma Despite Fulminant Epstein-Barr Virus Infection in Patients with XIAP Deficiency

Yizhe Sun, Janet S. Chou, Kevin D. Dong, Steven P. Gygi et autres

Abstract X-linked Lymphoproliferative Syndromes (XLP), which arise from mutations in the SH2D1A or XIAP genes, are characterized by the inability to control Epstein-Barr Virus (EBV) infection. While primary EBV infection triggers severe diseases in each, lymphomas occur at high rates with XLP-1 …

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