Subcellular Localization Signals of bHLH-PAS Proteins: Their Significance, Current State of Knowledge and Future Perspectives

Abstract

The bHLH-PAS (basic helix-loop-helix/ Period-ARNT-Single minded) proteins are a family of transcriptional regulators commonly occurring in living organisms. bHLH-PAS members act as intracellular and extracellular “signals” sensors, initiating response to endo- and exogenous signals, including toxins, redox potential, and light. The activity of these proteins as transcription factors depends on nucleocytoplasmic shuttling: the signal received in the cytoplasm has to be transduced, via translocation, to the nucleus. It leads to the activation of transcription of particular genes and determines the cell response to different stimuli. In this review, we aim to present the current state of knowledge concerning signals that affect shuttling of bHLH-PAS transcription factors. We summarize experimentally verified and published nuclear localization signals/nuclear export signals (NLSs/NESs) in the context of performed in silico predictions. We have used most of the available NLS/NES predictors. Importantly, all our results confirm the existence of a complex system responsible for protein localization regulation that involves many localization signals, which activity has to be precisely controlled. We conclude that the current stage of knowledge in this area is still not complete and for most of bHLH-PAS proteins an experimental verification of the activity of further NLS/NES is needed.

The Participation of the Intrinsically Disordered Regions of the bHLH-PAS Transcription Factors in Disease Development

“…Also, C-termini of Hif-1α and Hif-2α contain conserved NLS and NES. For SIM2 C-terminal region cytoplasmic localization was documented [111]. Finally, we demonstrated previously the presence of overlapping NES and NLS in the C-terminal region of NPAS4 [112].…”

Purification of an insect juvenile hormone receptor complex enables insights into its post-translational phosphorylation

“…This situation differs from the case of AHR, where phosphorylation of Ser residues straddling a bipartite NLS, located near the N-terminus of AHR, inhibited nuclear import (73). Mammalian cell lines have clearly provided valuable experimental systems for demonstration of NLS activity of insect proteins in the present and other studies (68)(69)(70). However, future investigation of phosphorylation-mediated modulation of NLS activity in more homologous systems may be warranted.…”

The role of α-ketoglutarate and the hypoxia sensing pathway in the regulation of pancreatic β-cell function

“… 83 Like HIF1α, neuronal PAS domain protein 4 (NPAS4) is a heterodimerization partner of HIF1β (or aryl hydrocarbon receptor nuclear translocator, ARNT). 84 In β-cells, the binding of HIF1α and NPAS4 to HIF1β is competitive, and each binding pair can activate a different subset of genes. 85 NPAS4 is rapidly induced by membrane depolarization and calcium influx by the calcineurin, Akt/protein kinase B, and Ca 2+ /calmodulin-dependent protein kinase signaling pathways in β-cells.…”