Protein aggregation as a cellular response to oxidative stress induced by heme and iron

Luiz R. C. Vasconcellos, Fabianno F. Dutra, Mariana S. Siqueira, Heitor A. Paula-Neto, Jennifer Dahan, Ellen Kiarely, Leticia A. M. Carneiro, Marcelo T. Bozza, and Leonardo H. Travassos

Proc Natl Acad Sci U S A. (2016) 113(47):E7474-E7482.

Speaker: Yu-Ling Chen (陳又菱)                                  Time: 14:10~15:00, Apr. 5, 2017

Commentator: Dr. Ai-Li Shiau (蕭璦莉 教授)            Place: Room 601

Abstract:

Infectious diseases that cause hemolysis are among the most fatal human diseases, such as β-thalassemia, sickle cell disease, ischemia-reperfusion, malaria, and dengue fever. Under these diseases, hemeproteins and heme are released, but whether heme affects the inflammatory response to microbial molecules remains to be investigated. Hemolysis and heme cooperate with microbial molecules for the induction of inflammatory cytokine production and inflammation in a mechanism dependent on ROS and Syk.¹ However, the mechanisms of eukaryotic cells respond to the toxic effects induced by heme to maintain homeostasis are not fully understood. So, the authors want to investigate the more detailed mechanisms that are induced by hemes. Under high levels of oxidative stress, autophagy is activated at later time points to clear LC3⁺ structures induced by heme and maintain cellular homeostasis. Then, the formation of p62/SQTM1 aggregates containing ubiquitinated proteins in structures is known as aggresome-like induced structures (ALIS) after autophagy-dependent degradation. Labile Fe released on hemes must be degraded to induce the formation of ALIS. Previous study has shown that Hp^- and Hx^- deficient mice develop increased renal damage after phenylhydrazine (PHZ)-induced hemolysis compared with wild-type animals. ² To test the hypothesis that such an increase in liberated free heme would induce ALIS formation in the damaged tissues in vivo, the authors compared PHZ-injected mice with saline-injected mice, and then observed a dramatic increase in p62 protein levels in kidneys, spleens, and livers of PHZ-injected mice. The results suggest that ALIS formation in response to high levels of free heme does occur in vivo.In conclusion, the formation of ALIS is a major part of cell response to high levels of free hemes, and has an important role in homeostasis maintenance.

References:

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Annu Rev Pharmacol Toxicol. 50:323-54 2010;50:323-54.

2.     Lim SK , Kim H, Lim SK, bin Ali A, Lim YK, Wang Y, Chong SM, Costantini F, Baumman H (1998). Increased Susceptibility in Hp Knockout Mice During Acute Hemolysis. Blood. 92(6):1870-7.