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Ca 2+ influx upon G protein-coupled receptor (GPCR) stimulation is observed as a cytosolic Ca 2+ concentration oscillation crucial to initiating downstream responses including cell proliferation, differentiation, and cell-cell communication. Although Jaw1 is known to interact with inositol 1,4,5-triphosphate receptor (ITPRs), Ca 2+ channels on the endoplasmic reticulum, the function of Jaw1 in the Ca 2+ dynamics with physiological stimulation remains unclear. In this study, using inducible Jaw1-expressing HEK293 cells, we showed that Jaw1 increases Ca 2+ influx by GPCR stimulation via changing the Ca 2+ influx oscillation pattern. Furthermore, we showed that Jaw1 increases the Ca 2+ release activity of all ITPR subtypes in a subtly different manner. It is well known that the Ca 2+ influx oscillation pattern varies from cell type to cell type, therefore these findings provide an insight into the relationship between the heterogeneous Ca 2+ dynamics and the specific ITPR and Jaw1 expression patterns., (© 2022. The Author(s).)

Jaw1/LRMP is a type II integral membrane protein that is localized at the endoplasmic reticulum (ER) and outer nuclear membrane. We previously reported that a function of Jaw1 is to maintain the nuclear shape as a KASH protein via its carboxyl terminal region, a component of linker of nucleoskeleton and cytoskeleton complex in the oligomeric state. Although the oligomerization of some KASH proteins via the cytosolic regions serves to stabilize protein-protein interactions, the issue of how the oligomerization of Jaw1 is regulated is not completely understood. Therefore, we focused on three distinct regions on the cytosolic face of Jaw1: the N-terminal region, the coiled-coil domain and the stem region, in terms of oligomerization. A co-immunoprecipitation assay showed that its coiled-coil domain is a candidate for the oligomerization site. Furthermore, our data indicated that the N-terminal region prevents the aberrant oligomerization of Jaw1 as an intrinsically disordered region (IDR). Importantly, the ectopic expression of an N-terminal region deleted mutant caused the formation of organized smooth ER (OSER), structures such as nuclear karmellae and whorls, in B16F10 cells. Furthermore, this OSER interfered with the localization of the oligomer and interactors such as the type III inositol 1,4,5-triphosphate receptor (IP 3 R3) and SUN2. In summary, the N-terminal region of Jaw1 inhibits the formation of OSER as an IDR to maintain the homeostatic localization of interactors on the ER membrane.

Jaw1/LRMP is characterized as a Type II integral membrane protein that is localized to endoplasmic reticulum, however, its physiological functions have been poorly understood. An alignment of amino acid sequence of Jaw1 with Klarsicht/ANC-1/Syne/homology (KASH) proteins, outer nuclear membrane proteins, revealed that Jaw1 has a partial homology to the KASH domain. Here, we show that the function of Jaw1 is to maintain nuclear shape in mouse melanoma cell line. The siRNA-mediated knockdown of Jaw1 caused a severe defect in nuclear shape, and the defect was rescued by ectopic expression of siRNA-resistant Jaw1. Since co-immunoprecipitation assay indicates that Jaw1 interacts with Sad-1/UNC-84 (SUN) proteins that are inner nuclear proteins and microtubules, this study suggests that Jaw1 has a role in maintaining nuclear shape via interactions with SUN proteins and microtubules.

Jaw1/LRMP is a membrane protein that is localized to the endoplasmic reticulum and outer nuclear membrane. Previously, we revealed that Jaw1 functions to maintain nuclear shape by interacting with microtubules as a Klarsicht/ANC-1/Syne/homology (KASH) protein. The loss of several KASH proteins causes defects in the position and shape of the Golgi apparatus as well as the nucleus, but the effects of Jaw1 depletion on the Golgi apparatus were poorly understood. Here, we found that siRNA-mediated Jaw1 depletion causes Golgi fragmentation with disordered ribbon structure in the melanoma cell, accompanied by the change in the localization of the Golgi-derived microtubule network. Thus, we suggest that Jaw1 is a novel protein to maintain the Golgi ribbon structure, associated with the microtubule network. [ABSTRACT FROM AUTHOR]