Iron, an essential metal element in human body, participants in a series of physiological processes, including the generation of red blood cells, oxygen storage and transportation, as well as immune response. Both iron overload and deficiency could trigger various diseases, thus the cellular iron homeostasis is under precise regulation. NCOA4, a dedicated autophagy receptor for mediating selective autophagy of ferritin (ferritinophagy),plays a vital role in maintaining cellular iron homeostasis. The cellular abundance of NCOA4 is regulated by the E3 ligase HERC2 that can specifically target NCOA4 for proteasomal degradation under iron-replete conditions. However, the detailed molecular mechanism governing the iron-dependent recognition of NCOA4 by HERC2 remains unclear.

In a recent study published in PNAS, a research team led by Professor PAN Lifeng at Shanghai Institute of Organic Chemistry of the Chinese Academy of Sciences systematically characterized the interaction between ferritinophagy receptor NCOA4 and HERC2. They discoveredthat the HERC2-binding domain (HBD) of NCOA4 harbors a [2Fe-2S] cluster, and can exist in two different states, the apo-form state and the [2Fe-2S] cluster-bound state. Moreover, they unraveled that HERC2 can effectively recognize the [2Fe-2S] cluster-bound NCOA4 HBD through its CPH and INBD domains with a synergistic binding mode. Subsequently, they solved, for the first time, the crystal structures of HERC2(2540-2700) and its complex with the [2Fe-2S] cluster-bound NCOA4 HBD. Importantly, the determined complex structure together with relevant biochemical and cellular results not only elucidated how NCOA4 HBD specifically senses cellular iron level by binding a [2Fe-2S] cluster, but also revealed the molecular basis underlying the specific interaction of HREC2 with the [2Fe-2S] cluster-bound NCOA4 HBD. Finally, based on their study and previous reports, they proposed a model to depict the regulation of NCOA4-mediated ferritinophagy by HERC2 in a [2Fe-2S] cluster-dependent manner for maintaining cellular iron homeostasis. In this model, when cellular iron is sufficient or overloaded, NCOA4 proteins tend to form aggregates, and their HBD domains are incorporated with [2Fe-2S] cluster likely owing to the elevated cellular biogenesis of iron-sulfur cluster. Upon insertion of the [2Fe-2S] cluster, the HBD domain of NCOA4 changes its conformation, which can be efficiently recognized by the CPH and INBD domains of the E3 ligase HERC2 through a unique mechanism uncovered in this study. After binding to the [2Fe-2S] cluster-bound NCOA4, HERC2 can further promote the K48-linked ubiquitination and the subsequent proteasomal degradation of NCOA4, thereby reducing the cellular protein abundance of NCOA4 as well as the NCOA4-mediated ferritinophagy to prevent more iron being released from ferritin to further increase the cellular iron level.

In summary, their findings discover, for the first time, that ferritinophagy receptor NCOA4 could bind one molecular of [2Fe-2S] cluster, and reveal the detailed molecular mechanism underpinning the iron-dependent recognition of NCOA4 by HERC2. This work also provides a new potential target for future drug development targeting iron homeostasis imbalance and related diseases.

Figure1. A proposed model of depicting the regulation of NCOA4-mediated ferritinophagy by HERC2 in a [2Fe-2S] cluster-dependent manner for maintaining cellular iron homeostasis. (Image by Prof. PAN Lifeng’s group)

PAN Lifeng, Ph.D. Professor

Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences

Ling Ling Road 345 Shanghai 200032 China

Tel: 0086-21-54925561

Email: panlf@sioc.ac.cn