Heme and iron induce protein aggregation

Abstract

Heme is an essential molecule expressed in many tissues where it plays key roles as the prosthetic group of several proteins involved in vital physiological and metabolic processes such as gas and electron transport. Structurally, heme is a tetrapyrrole ring containing an atom of iron (Fe) in its center. When released into the extracellular milieu, heme exerts several deleterious effects, which make it an important player in infectious and noninfectious hemolytic diseases where large amounts of free heme are observed such as malaria, dengue fever, β-thalassemia, sickle cell disease and ischemia-reperfusion. Our recent work has uncovered an unappreciated cellular response triggered by heme or Fe, one of its degradation products, on macrophages, which is the formation of protein aggregates known as aggresome-like induced structres (ALIS). This response was shown to be fully dependent on ROS production and the activation of the transcription factor NFE2L2/NRF2. In addition, we have demonstrated that heme degradation by HMOX1/HO-1 (heme oxygenase 1) is required and that Fe is essential for the formation of ALIS, as heme analogs lacking the central atom of Fe are not able to induce these structures. ALIS formation is also observed in vivo, in a model of phenylhydrazine (PHZ)-induced hemolysis, indicating that it is an integral part of the host response to excessive free heme and that it may play a role in cellular homeostasis.

Keywords: ALIS; NRF2; aggregation; autophagy; ferritin; heme; iron; oxidative stress; protein.

Figure 1.

Autophagy and ferritin control ALIS formation. Upon heme stimulation, HMOX1 degrades heme into carbon oxide, biliverdin and iron (Fe). In such conditions, ferritin is upregulated and neutralizes labile Fe, restraining ROS generation and consequently SQSTM1 upregulation and ALIS formation. Autophagy (AP) is also increased to avoid the accumulation of protein aggregates (left). In autophagy- (middle) or ferritin-deficient cells (right) we observe the accumulation of ALIS or the increase in ROS that in its turn activates NFE2L2 to increase the expression levels of SQSTM1, culminating with ALIS formation.