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LRRK2 signaling under these conditions requires its established Rab-binding surfaces, with Rab12 contributing significantly to this response. This pathway operates independently of CASM. In contrast, lysosomal stresses that induce CASM require both Rab-binding sites on LRRK2 and GABARAP for robust LRRK2 signaling. These findings identify ClC-7\u2013dependent lysosomal remodeling and Rab accumulation as key features linking PIKfyve inhibition to LRRK2 signaling and reveal that distinct lysosomal stresses engage different combinations of Rab and GABARAP inputs to activate LRRK2.<\/jats:p>","DOI":"10.1083\/jcb.202511137","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T15:30:19Z","timestamp":1792510219000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["ClC-7 links PIKfyve inhibition to Rab-dependent LRRK2 activity at lysosomes"],"prefix":"10.1083","volume":"225","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9522-168X","authenticated-orcid":true,"given":"Devin","family":"Clegg","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03v76x132","id-type":"ROR","asserted-by":"publisher"}],"name":"Yale University School of Medicine 1 Departments of Cell Biology, , New 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