Abstract
Transferrin receptor-1 (TfR1) has essential iron transport and proposed signal transduction functions. Proper TfR1 regulation is a requirement for hematopoiesis, neurological development, and the homeostasis of tissues including the intestine and muscle, while dysregulation is associated with cancers and immunodeficiency. TfR1 mRNA degradation is highly regulated, but the identity of the degradation activity remains uncertain. Here, we show with gene knockouts and siRNA knockdowns that two Roquin paralogs are major mediators of iron-regulated changes to the steady-state TfR1 mRNA level within four different cell types (HAP1, HUVEC, L-M, and MEF). Roquin is demonstrated to destabilize the TfR1 mRNA, and its activity is fully dependent on three hairpin loops within the TfR1 mRNA 3'-UTR that are essential for iron-regulated instability. We further show in L-M cells that TfR1 mRNA degradation does not require ongoing translation, consistent with Roquin-mediated instability. We conclude that Roquin is a major effector of TfR1 mRNA abundance.