The Transcription Factor Function of Parkin: Breaking the Dogma

Abstract

PRKN (PARK2) is a key gene involved in both familial and sporadic Parkinson's disease that encodes parkin (PK). Since its discovery by the end of the 90s, both functional and more recently, structural studies led to a consensual view of PK as an E3 ligase only. It is generally considered that this function conditions the cellular load of a subset of cytosolic proteins prone to proteasomal degradation and that a loss of E3 ligase function triggers an accumulation of potentially toxic substrates and, consequently, a neuronal loss. Furthermore, PK molecular interplay with PTEN-induced kinase 1 (PINK1), a serine threonine kinase also involved in recessive cases of Parkinson's disease, is considered to underlie the mitophagy process. Thus, since mitochondrial homeostasis significantly governs cell health, there is a huge interest of the scientific community centered on PK function. In 2009, we have demonstrated that PK could also act as a transcription factor (TF) and induces neuroprotection via the downregulation of the pro-apoptotic and tumor suppressor factor, p53. Importantly, the DNA-binding properties of PK and its nuclear localization suggested an important role in the control of several genes. The duality of PK subcellular localization and of its associated ubiquitin ligase and TF functions suggests that PK could behave as a key molecular modulator of various physiological cellular signaling pathways that could be disrupted in pathological contexts. Here, we update the current knowledge on PK direct and indirect TF-mediated control of gene expression.

Keywords: DNA binding; Parkinson’s disease; gene control; parkin; structure; transcription factor; ubiquitin ligase.

FIGURE 1

Overview of various mechanisms governing PK-mediated direct or indirect gene regulation. It summarizes the various mechanisms underlying direct or indirect PK-mediated gene regulation as extensively described in the “PK gene targets and associated biological functions” paragraph. Abbreviations that were not already described in the main text include Aph1 (anterior pharynx defective), Pen2 (presenilin enhancer-2), and AICD (Amyloid precursor protein intracellular domain). Red, blue, and black arrows indicate repression, activation, and yet unknown gene control phenotypes, respectively.