Regulation Of Iron Homeostasis By SPAK-Dependent Modulation Of FBXL5 Stability

Abstract

Intracellular iron homeostasis is regulated by a proteolytic switch whereby the E3 ubiquitin ligase FBXL5 targets iron regulatory proteins (IRPs) for ubiquitin-dependent degradation in iron-replete conditions while it is itself degraded during iron deficiency allowing IRPs to accumulate and regulate their downstream RNA targets. The cellular pathways that control FBXL5 degradation in low iron conditions are not well understood. Here, we report the identification of the STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) as a novel regulator of FBXL5 stability. We find that SPAK, a kinase previously implicated in osmotic stress regulation, regulates intracellular iron homeostasis through its physical association with FBXL5. This role is dependent on its kinase activity as overexpression of constitutively active SPAK increases FBXL5 poly-ubiquitination and degradation. Through this work, we have discovered a novel role for SPAK that extends beyond its well-established function in salt homeostasis and raises the possibility for signaling crosstalk between iron homeostatic and osmotic regulatory pathways.