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Excerpt from reviews: JBC


A new player involved in the response to kidney damage. The role of Kaposi’s sarcoma-associated herpesvirus in kinase pathway activation. Understand what a linker does in heme extraction. Check out these articles recently published in the Journal of Biological Chemistry.

A new player involved in the response to kidney damage

Fibrosis involves the excessive buildup of extracellular matrix, which can lead to loss of function when normal tissue is replaced by scar tissue, such as after injury. In the case of kidney disease in particular, fibrosis is the final stage of chronic disease characterized by the accumulation of interstitial fibroblasts and myofibroblasts in addition to the accumulation of ECM.

Carl Zeiss Microscopy

Microscopy image of a mouse kidney section.

Follistatin-like 1 is a secreted protein. While the role FSTL1 plays in heart and lung injury and the development of fibrosis has been widely studied, the role this protein plays in kidney injury and progression to chronic disease remains to be determined.

In a recent article in the Journal of Biological ChemistryYu Zhang and colleagues from the School of Biomedical Sciences at the Chinese University of Hong Kong and the Center of Nephrology and Urology at Sun Yat-sen University in China report that FSTL1 plays a profibrotic role in the kidney.

The team used several molecular biology and imaging techniques – including single-cell RNA-Seq analysis and immunofluorescence – to show that Fstl1 was enriched in stromal cells in obstructed mouse kidneys and that the FSTL1 expression was induced in fibroblasts during renal fibrogenesis in mice and humans. the patients.

Furthermore, the authors showed that overexpression of FSTL1 increased renal fibrosis and activated the Wnt/beta-catenin signaling pathway, while inhibition of FSTL1 decreased Wnt/β-catenin signaling.

Role of a viral oncoprotein in the activation of the kinase pathway

Kaposi’s sarcoma-associated herpes virus is the main etiological agent of Kaposi’s sarcoma, which manifests as patchy cancerous tumors on the skin and mucous membranes. It most often affects people with immune deficiencies, such as those with HIV/AIDS.

The virus – known as KSHV and human herpesvirus 8 – belongs to the same family as the Epstein-Barr virus, which is responsible for infectious mononucleosis and several types of cancer and has recently been implicated in the development of sclerosis in plates.

The virally encoded oncoprotein vFLIP is known to upregulate inhibitor kappa B kinase, or IKK complex, activating the canonical nuclear factor κB signaling pathway, a major factor in the pathogenesis of KSHV.

The physical interaction of vFLIP and the regulatory component of IKK kinase, IKK gamma, is essential for persistent activation and has been extensively studied; however, how the kinase subunits are mechanically active remains to be determined.

In a recent Journal of Biological Chemistry article, Claire Baggris, Swathi L. Senthil Kumar and collaborators from the Institute of Structural Molecular Biology in London report that vFLIP alone is sufficient to activate the IKK kinase complex. The researchers used a combination of cell-based assays and biophysical and structural biology techniques.

The authors also found weakly stabilized and high molecular weight vFLIP-IKKγ assemblies relevant to the activation process.

Ultimately, this new study determined that vFLIP-induced NF-κB activation relies on structurally specific vFLIP–IKKγ multimers that are essential for activating kinase subunits through autophosphorylation.

The proof is in the linker

Iron acts as an electron carrier and cofactor in many proteins; this makes it an essential nutrient for living organisms, including pathogenic bacteria such as Staphylococcus aureus, responsible for fatal nosocomial infections.

The iron-regulated surface determinant system is a family of proteins that sequesters iron from the host to support bacterial growth and is therefore a potential therapeutic target. The IsdH surface protein consists of three iron-like transporter domains, or NEATs, linked by linkers, and is responsible for hemoglobin uptake.

In a recent Journal of Biological Chemistry articleSandra Valenciano-Bellido and her colleagues at the University of Tokyo characterized the binding region between the NEAT2 and NEAT3 domains using several biophysical techniques to better understand the role it plays in heme extraction.

The researchers showed that the binding region contributes to the stability of the bound protein and this, in turn, influences the flexibility and orientation of the NEAT3 domain in its interaction with hemoglobin.

The authors suggest that this model explains how the binding region facilitates the positioning of NEAT3 to sequester heme, and they argue that the study adds to researchers’ understanding of the mechanism of heme extraction from human hemoglobin. by IsdH.