bims-stacyt 2021-03-28 papers

J Biol Chem. 2021 Mar 23. pii: S0021-9258(21)00364-1. [Epub ahead of print] 100584

VEGF and VEGFR2 bind to similar pH-sensitive sites on fibronectin, exposed by heparin-mediated conformational changes.

Mattia Usuelli, Timmy Meyer, Raffaele Mezzenga, Maria Mitsi.

Physical interactions between vascular endothelial growth factor (VEGF), a central player in blood endothelial cell biology, and fibronectin, a major fibrillar protein of the extracellular matrix, are important determinants of angiogenic activity in health and disease. Conditions signaling the need for new blood vessel growth, such as hypoxia and low extracellular pH, increase VEGF-fibronectin interactions. These interactions can be further fine-tuned through changes in the availability of the VEGF binding sites on fibronectin, regulated by conformational changes induced by heparin and heparan sulfate chains within the extracellular matrix. These interactions may alter VEGF bioavailability, generate gradients, or alter the way VEGF is recognized by and activates its cell-surface receptors. Here, using equilibrium and kinetic studies, we discovered that fibronectin can also interact with the extracellular domain of the VEGF receptor 2 (VEGFR2). The VEGFR2 binding sites on fibronectin show great similarity to the VEGF binding sites, as they were also exposed upon heparin-induced conformational changes in fibronectin, and the interaction was enhanced at acidic pH. Kinetic parameters and affinities for VEGF and VEGFR2 binding to fibronectin were determined by surface plasmon resonance measurements, revealing two populations of fibronectin binding sites for each molecule. Our data also suggest that a VEGF/VEGFR2/fibronectin triple complex may be formed by VEGF or VEGFR2 first binding to fibronectin and subsequently recruiting the third binding partner. The formation of such a complex may lead to the activation of distinct angiogenic signaling pathways, offering new possibilities for clinical applications that target angiogenesis.

Keywords: VEGFR2; Vascular Endothelial Growth Factor (VEGF); acidic; angiogenesis; extracellular matrix; fibronectin; heparin; hypoxia; surface plasmon resonance (SPR)

DOI: https://doi.org/10.1016/j.jbc.2021.100584

Immunity. 2021 Mar 19. pii: S1074-7613(21)00115-1. [Epub ahead of print]

The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts.

Arthritis typically involves recurrence and progressive worsening at specific predilection sites, but the checkpoints between remission and persistence remain unknown. Here, we defined the molecular and cellular mechanisms of this inflammation-mediated tissue priming. Re-exposure to inflammatory stimuli caused aggravated arthritis in rodent models. Tissue priming developed locally and independently of adaptive immunity. Repeatedly stimulated primed synovial fibroblasts (SFs) exhibited enhanced metabolic activity inducing functional changes with intensified migration, invasiveness and osteoclastogenesis. Meanwhile, human SF from patients with established arthritis displayed a similar primed phenotype. Transcriptomic and epigenomic analyses as well as genetic and pharmacological targeting demonstrated that inflammatory tissue priming relies on intracellular complement C3- and C3a receptor-activation and downstream mammalian target of rapamycin- and hypoxia-inducible factor 1α-mediated metabolic SF invigoration that prevents activation-induced senescence, enhances NLRP3 inflammasome activity, and in consequence sensitizes tissue for inflammation. Our study suggests possibilities for therapeutic intervention abrogating tissue priming without immunosuppression.

Keywords: arthritis; cell metabolism; cellular senescence; complement system; inflammasome; inflammation; mechanistic target of rapamycin; synovial fibroblasts; tissue priming; trained immunity

DOI: https://doi.org/10.1016/j.immuni.2021.03.003

Nat Metab. 2021 Mar;3(3): 410-427

TFEB-GDF15 axis protects against obesity and insulin resistance as a lysosomal stress response.

Jinyoung Kim, Seong Hun Kim, Hyereen Kang, Soyeon Lee, Shi-Young Park, Yoonil Cho, Yu-Mi Lim, Ji Woong Ahn, Young-Hwan Kim, Seungsoo Chung, Cheol Soo Choi, Yeon Jin Jang, Hye Soon Park, Yoonseok Heo, Kook Hwan Kim, Myung-Shik Lee.

TFEB, a key regulator of lysosomal biogenesis and autophagy, is induced not only by nutritional deficiency but also by organelle stress. Here, we find that Tfeb and its downstream genes are upregulated together with lipofuscin accumulation in adipose tissue macrophages (ATMs) of obese mice or humans, suggestive of obesity-associated lysosomal dysfunction/stress in ATMs. Macrophage-specific TFEB-overexpressing mice display complete abrogation of diet-induced obesity, adipose tissue inflammation and insulin resistance, which is independent of autophagy, but dependent on TFEB-induced GDF15 expression. Palmitic acid induces Gdf15 expression through lysosomal Ca2+-mediated TFEB nuclear translocation in response to lysosomal stress. In contrast, mice fed a high-fat diet with macrophage-specific Tfeb deletion show aggravated adipose tissue inflammation and insulin resistance, accompanied by reduced GDF15 level. Finally, we observe activation of TFEB-GDF15 in ATMs of obese humans as a consequence of lysosomal stress. These findings highlight the importance of the TFEB-GDF15 axis as a lysosomal stress response in obesity or metabolic syndrome and as a promising therapeutic target for treatment of these conditions.

DOI: https://doi.org/10.1038/s42255-021-00368-w