{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T06:38:55Z","timestamp":1763707135180,"version":"3.45.0"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Mast cells (MCs) mediate immune, allergic, and neuroinflammatory responses by releasing inflammatory mediators upon activation through the immunoglobulin E (IgE) receptor Fc\u03b5RI or innate stimuli acting through Mas-related G protein coupled receptors (Mrgprs). We previously showed that Rab12 negatively regulates mediator release by recruiting the Rab-interacting lysosomal protein (RILP)-dynein complex to the secretory granules (SGs). Because Rab12 also interacts with the RILP-like proteins RILP-L1 and RILP-L2, we examined whether phosphorylation controls Rab12 distribution among its RILP family effectors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Pulldown assays were used to compare the effects of MC activation on Rab12 interactions with its effectors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Here we show that activation by either IgE\/antigen or the neuropeptide substance P, which binds to MRGPRX2, induces phosphorylation of the Rab GTPases Rab7 and Rab12. Phosphorylation of both GTPases was sensitive to protein kinase C (PKC) inhibition but resistant to inhibition of the leucine-rich repeat kinase 2 (LRRK2), a known Rab12 phosphorylating kinase. Furthermore, knockdown of the Leucine-Rich Repeat kinase 1 (LRRK1) suppressed phosphorylation of both Rab7 and Rab12, implicating LRRK1 in their phosphorylation by a PKC-dependent mechanism. Like phosphorylation by LRRK2, LRRK1-mediated phosphorylation of Rab12 increased its affinity for RILP-L1 and RILP-L2 while reducing binding to RILP. In contrast, LRRK1 phosphorylation of Rab7 enhanced its affinity for RILP.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1709196","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T06:30:04Z","timestamp":1763706604000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Phosphorylation-driven effector switching of Rab7 and Rab12 by the leucine-rich repeat kinase 1 in mast cells"],"prefix":"10.3389","volume":"16","author":[{"given":"Jana","family":"Omar-Kabha","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sewar","family":"Omari","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaara","family":"Gorzalczany","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatima","family":"Amer-Sarsour","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth","family":"Kleeblatt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitsunori","family":"Fukuda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Avraham","family":"Ashkenazi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ronit","family":"Sagi-Eisenberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.jdermsci.2007.09.009","article-title":"Mast 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