Seminar by Prof. Rachel Nechushtai

The Hebrew University of Jerusalem (Israel)

NAF-1, a NEET 2Fe-2S Protein, Involvement in Different Diseases

Nutrient-Deprivation Autophagy Factor-1 (NAF-1; encoded by CISD2), belongs to a novel family of iron sulfur(2Fe-2S) proteins defined by a unique NEET fold and a labile iron sulfur cluster. Localized to the ER, mitochondria and their interacting membranes, NAF-1 was implicated in the regulation of BCL-2- Beclin-1-BIK-dependent autophagy, BCL-2- and Calpain-2-dependent apoptosis, ER-calcium signaling and iron and ROS homeostasis. NAF-1 was also linked to neurodegenerative diseases, skeletal muscle maintenance, and aging , and an intragenic deletion in the NAF-1 gene, as well as a point mutation leading to a transcriptional splicing error of NAF-1, lead to a rare but serious disease called Wolfram Syndrome 2 (WFS2) which is associated with hearing deficiencies, severe blindness, diabetes and reduced life expectancy. Although recent studies identified a potential role for NAF-1 in the development of several different cancers, its role in the progression of these diseases is currently unknown. In this lecture I will report that NAF-1 levels are elevated in primary human invasive ductal carcinomas (IDCs) and lymph node metastases, and that overexpression of NAF-1 [NAF-1(+)] in xenograft human epithelial breast tumors rapidly accelerates their growth. We further showed, using immunohistochemistry and proteomic analyses, that xenograft NAF-1(+) tumors have enhanced levels of proteins involved in cell proliferation and ROS detoxification, and suppressed levels of proteins involved in apoptosis and DNA damage. Moreover, we found that NAF-1 overexpression confers marked resistance to oxidative stress, thereby preventing cell death and inducing tumor growth. A comparative study of the protein networks identified in NAF-1(+) xenograft tumors, and those found in clinical tumors obtained from patients, further revealed that enhanced NAF-1 expression is linked with elevated expression of multiple proteins involved in ROS detoxification. The findings in WFS2 patient's fibroblasts (skin cells) indicated mitochondrial iron and ROS accumulation. These pathological phenotypes were repaired by treating the cells with a chelating agent.