A subcellular map of the human proteome

Thul, Peter; Åkesson, Lovisa; Wiking, Mikaela; Mahdessian, Diana; Geladaki, Aikaterini; Blal, Hammou Ait; Alm, Tove; Asplund, Anna; Björk, Lars; Breckels, Lisa M.; Bäckström, Anna; Danielsson, Frida; Fagerberg, Linn; Fall, Jenny; Guy, Laurent; Gnann, Christian; Hober, Sophia; Hjelmare, Martin; Johansson, Fredric; Lee, Sunjae; Lindskog, Cecilia; Mulder, Jan; Mulvey, Claire M.; Nilsson, Peter; Oksvold, Per; Rockberg, Johan; Schutten, Rutger; Schwenk, Jochen M.; Sivertsson, Åsa; Sjöstedt, Evelina; Skogs, Marie; Stadler, Charlotte; Sullivan, Devin P.; Tegel, Hanna; Winsnes, Casper F.; Zhang, Cheng Cheng; Zwahlén, Martin; Mardinoğlu, Adil; Pontén, Fredrik; Feilitzen, Kalle von; Lilley, Kathryn S.; Uhlén, Mathias; Lundberg, Emma

doi:10.1126/science.aal3321

Cited by 2,367 publications

(2,293 citation statements)

References 66 publications

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“…To test this, we employed A549 cells, which upregulate mPGES-1 in response to IL-1β stimulation (34). Importantly, A549 cells express FABP5 but do not express other FABP isoforms, thus providing an ideal system to examine the contribution of FABP5 toward mPGES-1 induction (38). We confirmed that treatment of A549 cells with IL-1β (1 ng/ml) results in the upregulation of mPGES-1 (Fig.…”

Section: Fabp5 Induces Mpges-1 Via Nf-kb-il-1βsupporting

confidence: 57%

“…Therefore, it is possible that FABP5 may regulate PGE2 biosynthesis in immune cells by shuttling arachidonic acid to COX-2, which is localized on the endoplasmic reticulum. To test this experimentally, human THP-1 monocytic cells, which express FABP5 but not other FABP isoforms (38), were differentiated into macrophages using phorbol myristate acetate and subsequently activated with lipopolysaccharide (LPS) to ensure robust PGE2 biosynthesis as described (39). Treatment with LPS for 24 h was required to induce COX-2 expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Fatty acid–binding protein 5 controls microsomal prostaglandin E synthase 1 (mPGES-1) induction during inflammation

Bogdan

Falcone

Kanjiya

et al. 2018

Journal of Biological Chemistry

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Fatty acid binding proteins (FABPs) are intracellular lipid carriers that regulate inflammation, and pharmacological inhibition of FABP5 reduces inflammation and pain. The mechanism(s) underlying the anti-inflammatory effects associated with FABP5 inhibition are poorly understood. Herein, we identify a novel mechanism through which FABP5 modulates inflammation. In mice, intraplantar injection of carrageenan induces acute inflammation that is accompanied by edema, enhanced pain sensitivity, and elevations in pro-inflammatory cytokines and prostaglandin E2 (PGE2). Inhibition of FABP5 reduced pain, edema, cytokine, and PGE2 levels. PGE2 is a major eicosanoid that enhances pain in the setting of inflammation and we focused upon the mechanism(s) through which FABP5 modulates PGE2 production. Cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (mPGES-1) are enzymes upregulated at the site of inflammation and account for the bulk of PGE2 biosynthesis. Pharmacological or genetic FABP5 inhibition suppressed the induction of mPGES-1 but not COX-2 in carrageenan-injected paws, which occurred predominantly in macrophages.The cytokine interleukin 1β (IL-1β) is a major inducer of mPGES-1 during inflammation. Using A549 cells that express FABP5, IL-1β stimulation upregulated mPGES-1 expression, and mPGES-1 induction was attenuated in A549 cells bearing a knockdown of FABP5. IL-1β upregulates mPGES-1 via NF-kB, which activates the mPGES-1 promoter. Knockdown of FABP5 reduced the activation and nuclear translocation of NF-kB, and attenuated mPGES-1 promoter activity. Deletion of NF-kB binding sites within the mPGES-1 promoter abrogated the ability of FABP5 to inhibit mPGES-1 promoter activation. Collectively, these results position FABP5 as a novel regulator of mPGES-1 induction and PGE2 biosynthesis during inflammation. ________________________________________ Pain is a frequent reason for seeking medical care and approximately thirty percent of older adults experience chronic pain (1-3). Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are mainstay treatments for chronic pain. However, chronic NSAID use is associated with gastrointestinal hemorrhage and even acute NSAID use increases the incidence of myocardial FABP5 regulates mPGES-1 during inflammation2 infarctions (4,5). Chronic opioid use is associated with significant addiction and overdose liability (6)(7)(8). Consequently, there is a need to develop novel efficacious non-opioid analgesics.Fatty acid binding proteins (FABPs) are intracellular carriers for fatty acids and related bioactive lipids such as the endocannabinoid anandamide (9-11). In addition to the cytosolic transport of lipids, FABPs deliver ligands to the nucleus wherein they activate nuclear receptors (10,(12)(13)(14). There are ten FABP isoforms expressed in mammals and we previously demonstrated that pharmacological inhibition of FABP5 produces analgesic effects by enhancing endocannabinoid signaling (15)(16)(17)(18). We also demonstrated that FABP5 is expressed in nociceptors, p...

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Section: Fabp5 Induces Mpges-1 Via Nf-kb-il-1βsupporting

confidence: 57%

Section: Resultsmentioning

confidence: 99%

Fatty acid–binding protein 5 controls microsomal prostaglandin E synthase 1 (mPGES-1) induction during inflammation

Bogdan

Falcone

Kanjiya

et al. 2018

Journal of Biological Chemistry

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“…In contrast, talin2 expression is more variable, and it is absent entirely from some cell types, for example, no talin2 is present in endothelial cells possibly via silencing of the Tln2 gene by promoter methylation 26, 27. The Human Protein Atlas 28 shows the near ubiquitous expression of talin1 in all cell types in all tissues, whereas the high levels of talin2 are found mainly in the brain, particularly the cerebral cortex, heart muscle and the kidney.…”

Section: The Talinsmentioning

confidence: 99%

The tale of two talins – two isoforms to fine‐tune integrin signalling

Gough

Goult

2018

FEBS Letters

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Talins are cytoplasmic adapter proteins essential for integrin‐mediated cell adhesion to the extracellular matrix. Talins control the activation state of integrins, link integrins to cytoskeletal actin, recruit numerous signalling molecules that mediate integrin signalling and coordinate recruitment of microtubules to adhesion sites via interaction with KANK (kidney ankyrin repeat‐containing) proteins. Vertebrates have two talin genes, TLN1 and TLN2. Although talin1 and talin2 share 76% protein sequence identity (88% similarity), they are not functionally redundant, and the differences between the two isoforms are not fully understood. In this Review, we focus on the similarities and differences between the two talins in terms of structure, biochemistry and function, which hint at subtle differences in fine‐tuning adhesion signalling.

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“…This value reflects the relative abundance difference of a protein compared to its cellular compartment (Fig 2B and Dataset EV3). Since many proteins are associated with more than one cellular compartment (on average, only 20% of the annotated proteins were specific to one compartment and 36% were annotated to two compartments, Fig EV1B; Thul et al , 2017), we wanted to assess the robustness of the linear models when taking into account multiple compartment annotations for the same proteins. Thus, we compared the CNV models built using all the proteins mapping to a given compartment to CNV models built using only proteins that are exclusive to a given compartment, so that there are no shared proteins between the linear models.…”

Section: Resultsmentioning

confidence: 99%

Quantifying compartment‐associated variations of protein abundance in proteomics data

Parca

Beck

Bork

et al. 2018

Molecular Systems Biology

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Quantitative mass spectrometry enables to monitor the abundance of thousands of proteins across biological conditions. Currently, most data analysis approaches rely on the assumption that the majority of the observed proteins remain unchanged across compared samples. Thus, gross morphological differences between cell states, deriving from, e.g., differences in size or number of organelles, are often not taken into account. Here, we analyzed multiple published datasets and frequently observed that proteins associated with a particular cellular compartment collectively increase or decrease in their abundance between conditions tested. We show that such effects, arising from underlying morphological differences, can skew the outcome of differential expression analysis. We propose a method to detect and normalize morphological effects underlying proteomics data. We demonstrate the applicability of our method to different datasets and biological questions including the analysis of sub‐cellular proteomes in the context of Caenorhabditis elegans aging. Our method provides a complementary perspective to classical differential expression analysis and enables to uncouple overall abundance changes from stoichiometric variations within defined group of proteins.

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A subcellular map of the human proteome

Cited by 2,367 publications

References 66 publications

Fatty acid–binding protein 5 controls microsomal prostaglandin E synthase 1 (mPGES-1) induction during inflammation

Fatty acid–binding protein 5 controls microsomal prostaglandin E synthase 1 (mPGES-1) induction during inflammation

The tale of two talins – two isoforms to fine‐tune integrin signalling

Quantifying compartment‐associated variations of protein abundance in proteomics data

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