Overview

The overall focus of the laboratory of Masao Kaneki, MD, PhD, at Massachusetts General Hospital is to understand the role of inflammatory/stress signaling cascades in the molecular pathogenesis in human diseases. Inflammation is implicated in a variety of human diseases, whereas it is a necessary and adaptive response to environmental or intrinsic stress. Thus, inflammation functions as a double-edged sword, and hence its activation needs to be tightly regulated.

Nonetheless, how inflammatory response is regulated or when it becomes pathogenic is not well understood. In this context, the major questions my research team has been trying to address include:

• How inflammatory response is amplified or sustained in the development of human diseases
• How inflammatory response is linked to metabolic alterations (e.g., the Warburg-like metabolic reprogramming)

We focus on cysteine thiol modifications, protein S-nitrosylation (the covalent attachment of nitric oxide to thiols) and farnresylation, as potential hubs of the nexus of positive feed-forward signaling networks that forms the inflammatory Warburg-like metabolic shift complex.

Research Projects

Inducible Nitric Oxide Synthase

Project 1 is to clarify how inducible nitric oxide synthase (iNOS), a major mediator of inflammation, causes or exacerbates obesity- and stress (e.g., burn)-induced insulin resistance and pancreatic β-cell dysfunction.

My research team has established the role of iNOS in obesity- and stress-induced insulin resistance. iNOS-mediated S-nitrosylation of Akt inactivates it (Akt is a key player in the metabolic actions of insulin [e.g., glucose uptake]).

In addition, iNOS decreases insulin receptor substrate (IRS)-1 and IRS-2 expression in skeletal muscle and liver in obese, diabetic mice and burned mice and in pancreatic β-cells.

The Kaneki laboratory has been the frontrunner on the role of iNOS in obesity- and burn-induced insulin resistance.

Inducible Farnesylation

In Project 2, the research in my laboratory has identified “inducible farnesylation” as a key component of inflammatory spiral and the Warburg-like metabolic shift.

The cholesterol-lowering independent pleiotropic beneficial effects of statins, inhibitors of HMG-CoA reductase, have attracted much scientific attention since the 1990s.

Dr. Kaneki posits that inhibition of farnesylation is a major mechanism of the pleiotropic beneficial effects of statins. His research team has shown that farnesyltransferase inhibitors (FTIs) improve the survival in murine models of endotoxemia, sepsis and acute fulminant hepatitis, and prevents atherogenesis in ApoE knockout mice and burn-induced insulin resistance in mice.

Moreover, he proposes the new concept of “inducible farnesylation,” where inflammation or stress induces de novo farnesylatoin in proteins that are not farnesylated or farnesylated to a small extent under basal conditions. This project is expected to aid the development of clinical trials of FTIs in inflammatory diseases, including critical illness (e.g., sepsis, burn).

Inflammatory Spirals

In Project 3, the Kaneki Lab is investigating the mechanisms of inflammatory spiral common to aging-related disorders. In aging-related disorders, including diabetes, aging-associated pneumonia and neurodegeneration, inflammation and cell death play crucial roles in the pathogenesis. Nonetheless, some important questions remain to be addressed.

The first such question is whether there are exist mechanisms common to the pathogenesis of a variety of aging-related disorders.

In a recent study, we have shown that iNOS-dependent S-nitrosylation of the Cys-X-X-Cys motifs in SIRT1, a NAD+-dependent deacetylase, inactivates SIRT1, and thereby increases acetylation and activity of p53 and p65 NF-κB in rodent models of sarcopenia, Parkinson’s disease and systemic inflammatory response syndrome.

Collectively, our study indicates that SIRT1 S-nitrosylation function as a pro-inflammatory switch that initiates and sustains the inflammatory spiral consisting of the iNOS→SIRT1 S-nitrosylation→activation of p53 and p65 NF-κB→iNOS.

Publications

Nakazawa H, Yamada M, Yu Y-M, Fischman AJ, Martyn JAJ, Ronald. G. Tompkins RG, KanekiM.Role of protein farnesylation in burn-induced metabolic derangements and insulin resistance in mouse skeletal muscle, PLOS ONE, 2015 Jan 16;10(1):e0116633. PMID: 25594415

Shinozaki S, Chang K, Sakai M, Shimizu N, Yamada M, Tanaka T, Nakazawa H, Ichinose F, Yamada Y, Ishigami A, Ito H, Ouchi Y, Starr ME, Saito H, Shimokado K, Stamler JS, Kaneki M.Inflammatory stimuli induce inhibitory S-nitrosylation of the deacetylase SIRT1 to increase acetylation and activation of p53 and p65. Sci Signal. 2014 Nov 11;7(351):ra106. PMID: 25389371

Tanioka T, Tamura Y, Fukaya M, Shinozaki S, Mao J, Kim M, Shimizu N, Kitamura T, Kaneki M.Inducible nitric-oxide synthase and nitric oxide donor decrease insulin receptor substrate-2 protein expression by promoting proteasome-dependent degradation in pancreatic beta-cells: involvement of glycogen synthase kinase-3beta. J Biol Chem. 2011 Aug 19;286(33):29388-96, PMID: 21700708

Yang W, Yamada M, Tamura Y, Chang K, Mao J, Zou L, Feng Y, Kida K, Scherrer-Crosbie M, Chao W, Ichinose F, Yu YM, Fischman AJ, Tompkins RG, Yao S, Kaneki M.Farnesyltransferase inhibitor FTI-277 reduces mortality of septic mice along with improved bacterial clearance. J Pharmacol Exp Ther. 2011 Dec;339(3):832-41. PMID: 21873557

Shinozaki S, Choi CS, Shimizu N, Yamada M, Kim M, Zhang T, Shiota G, Dong HH, Kim YB, Kaneki M.Liver-specific inducible nitric-oxide synthase expression is sufficient to cause hepatic insulin resistance and mild hyperglycemia in mice. J Biol Chem. 2011 Oct 7;286(40):34959-75. PMID: 21846719;

Yasukawa T, Tokunaga E, Ota H, Sugita H, Martyn JA, Kaneki M.S-nitrosylation-dependent inactivation of Akt/protein kinase B in insulin resistance. J Biol Chem. 2005 Mar 4;280(9):7511-8. PMID: 15632167 

Sugita H, Fujimoto M, Yasukawa T, Shimizu N, Sugita M, Yasuhara S, Martyn JA, Kaneki M.Inducible nitric-oxide synthase and NO donor induce insulin receptor substrate-1 degradation in skeletal muscle cells. J Biol Chem. 2005 Apr 8;280(14):14203-11. PMID: 15805118