PLEKHM2 is a critical adaptor protein that regulates lysosomal trafficking and positioning through its interaction with the small GTPase ARL8B 1. It recruits kinesin-1 to lysosomal membranes, directing their movement toward microtubule plus ends and enabling peripheral localization 12. Beyond lysosomal dynamics, PLEKHM2 maintains Golgi apparatus organization 1 and drives polarization of cytolytic granules and microtubule-organizing centers during NK cell-mediated cytotoxicity 2. PLEKHM2 function is regulated by programmed ribosomal frameshifting, which generates an alternative protein isoform that relieves autoinhibition and enables ARL8-independent cellular trafficking 3. Both canonical and frameshifted proteins are necessary for normal cardiac contractility 3. Clinically, PLEKHM2 mutations cause early-onset dilated cardiomyopathy and left ventricular noncompaction through impaired autophagy and mitochondrial clearance 45. Loss of PLEKHM2 function leads to perinuclear lysosome accumulation, autophagy flux impairment, and accumulation of damaged mitochondria generating excessive reactive oxygen species 56. PLEKHM2 also plays roles in neuronal development and immune pathogen restriction 67, and has been identified as a potential genetic susceptibility marker for familial lung adenocarcinoma 8.