Targeting of the type II inositol polyphosphate 5-phosphatase INPP5B to the early secretory pathway

The inositol polyphosphate 5-phosphatase INPP5B is closely related to the Lowe syndrome protein OCRL1, sharing a similar substrate specificity, domain organisation and an ability to compensate for loss of OCRL1 in knockout mice. The cellular localisation and functions of INPP5B have remained poorly defined until recently, when a role within the endocytic pathway was suggested. Here, we report that INPP5B is also localised to the early secretory pathway including the Golgi apparatus and ER-to-Golgi intermediate compartment (ERGIC). Consistent with this localisation, INPP5B binds to specific RAB proteins within the secretory pathway, and mutational analysis indicates that RAB binding is required for efficient Golgi targeting of INPP5B. Unlike OCRL1, INPP5B interacts with neither clathrin nor -adaptin and is largely absent from clathrin-coated intermediates. Expression of INPP5B but not OCRL1 alters the distribution of the cycling protein ERGIC53 when cells are incubated at low temperature (15°C) or in the presence of brefeldin A, causing ERGIC53 to accumulate in the ERGIC, with a concomitant loss from the ER. Our data suggest a role for INPP5B in retrograde ERGIC-to-ER transport and imply that it has functions distinct from those of OCRL1 within both the secretory and endocytic pathways.