Protein pyrophosphorylation: moving forward.

Adolfo Saiardi

doi:10.1042/bcj20160710c

Abstract

Genetic ablation of inositol pyrophosphate synthesis has established the fundamental importance of this class of molecules to the eukaryote cell. These studies, however, must be complemented by cell biology and biochemical approaches to appreciate the signalling involved in the processes regulated by inositol pyrophosphates. A recent study by Chanduri et al. published in the Biochemical Journal, by integrating multiple experimental approaches, demonstrated that inositol pyrophosphates regulate intracellular vesicular movement. In particular, the vesicular transport along the microtubule that is driven by the motor protein complex dynein. Importantly, one subunit of this cellular motor, dynein 1 intermediate chain 2, undergoes serine pyrophosphorylation, a post-translational modification driven by inositol pyrophosphates. The pyrophosphorylation status of this dynein intermediate chain regulates its interaction with dynactin, which recruits the motor to vesicles. This mechanistically might explain how inositol pyrophosphates control intracellular membrane trafficking. By dissecting the serine pyrophosphorylation process, this work increases our awareness of this modification, underappreciated by the scientific literature but probably not by the eukaryotic cell.

Highlights

The ever-growing interest in the inositol pyrophosphates as signalling and metabolic messengers is fully justified by the many unique and exciting features this class of molecule possesses
Studying the co-localization of transferrin with the early endosomal marker early endosome antigen 1 (EEA1) revealed that the degree of EEA1–transferrin co-localization was higher in ip6k1−/− mouse embryonic fibroblast (MEF) compared with ip6k1+/+ MEFs
Chanduri et al [9] have tracked vesicular movement in vivo using a specific fluorescence sensor, demonstrating that the speed of fluorescent endosomes is significantly lower in ip6k1−/− MEFs

Summary

Introduction

The ever-growing interest in the inositol pyrophosphates as signalling and metabolic messengers is fully justified by the many unique and exciting features this class of molecule possesses. Studies indicate that inositol pyrophosphates regulate basic metabolism [1,2] such as cellular energetics [3] or phosphate homeostasis [4,5]. This indicates that transferrin’s exit from early endosomes is delayed in ip6k1−/− MEFs. The expression of active, but not inactive, IP6K1 rescued these defects, demonstrating that inositol pyrophosphates are required for endosomal sorting of transferrin and its accumulation in the ERC.

Results

Conclusion