PIP₃ phosphatase inositol polyphosphate 5-phosphatase K (INPP5K) connects the endoplasmic reticulum to microtubules and mediates the regulation of endoplasmic reticulum morphology

Abstract

Inositol polyphosphate 5-phosphatase K (INPP5K) is an endoplasmic reticulum (ER)-residing phosphoinositide 5-phosphatase that de-phosphorylates PI(4,5)P₂, thereby regulating ER morphology. Here, we show that INPP5K interacts with β-tubulin through its 5-phosphatase domain and localizes to microtubules. A cluster of basic amino acids within the 5-phosphatase domain of INPP5K is responsible for this interaction. Alteration of these amino acids to alanine (INPP5K 4A mutant) abolished INPP5K localization to the ER. Expression of the INPP5K 4A mutant induced ER swelling and the withdrawal of ER tubules. Taken together, these findings suggest that INPP5K connects the ER to microtubules and regulates ER morphology.