PLEKHM2

PLEKHM2 (SKIP) is an autoinhibited lysosomal adaptor that couples lysosomes and related organelles to plus-end-directed microtubule motors for anterograde transport toward the cell periphery (PMID:22172677, PMID:33232665). It is recruited to the lysosomal membrane by GTP-bound ARL8, where it engages kinesin-1 through two kinesin light chain-binding motifs to drive lysosomes away from the microtubule-organizing center (PMID:22172677); recruitment and motor coupling are gated by an intramolecular interaction in which the C-terminal PH domains fold back onto the N-terminal ARL8/kinesin-binding region, an inhibition that ARL8 binding relieves, with a middle disordered region mediating self-association that enhances kinesin-1 engagement (PMID:33232665). Beyond kinesin-1, SKIP recruits and activates kinesin-3 (KIF1Bβ) on a subset of lysosomes (PMID:34878110), and on melanosomes it acts as a Rab1A-specific effector to assemble a Rab1A–SKIP–kinesin-1 transport complex, making it a shared motor adaptor across organelle classes (PMID:25649263). A conserved +1 programmed ribosomal frameshift generates a second proteoform bearing a novel C-terminal alpha-helix that constitutively relieves autoinhibition and permits peripheral movement independent of ARL8 (PMID:41134891). SKIP additionally binds monophosphorylated phosphoinositides, accumulating at PtdIns(4)P-rich sites to drive lysosomal tubulation during phagolysosome resolution (PMID:31570833), recruits HOPS tethering subunits to peripheral lysosomes (PMID:25908847), and participates in Rab9-dependent retrograde MPR trafficking (PMID:23162002). Loss of PLEKHM2 causes perinuclear collapse of lysosomes and endosomes with impaired autophagic flux (PMID:26464484), and in cardiomyocytes leads to accumulation of damaged mitochondria, elevated ROS, and reduced contractility (PMID:38490981); a homozygous frameshift mutation in PLEKHM2 causes a human disease with these cellular trafficking and autophagy defects (PMID:26464484).

1. 2011 High

   Established the core mechanism by which lysosomes move to the cell periphery, identifying SKIP as the ARL8-GTP effector that links lysosomes to kinesin-1.

   Evidence Affinity chromatography of ARL8-GTP, RNAi of ARL8 and SKIP with lysosome distribution readout, and mutagenesis of KLC-binding motifs

   PMID:22172677

   Open questions at the time

   • Did not resolve how the SKIP-kinesin interaction is regulated or switched off
   • Structural basis of ARL8-SKIP binding not defined
2. 2011 Low

   Screening of RUN-domain proteins against Rabs nominated Rab1A as a SKIP RUN-domain partner, hinting at organelle targeting beyond ARL8.

   Evidence Genome-wide yeast two-hybrid of the PLEKHM2 RUN domain against 60 Rab isoforms

   PMID:21737958

   Open questions at the time

   • Single yeast two-hybrid with no mammalian biochemical validation in this study
   • Functional role of the interaction not established here
3. 2012 High

   Revealed a retrograde-trafficking role for SKIP and how a bacterial effector hijacks it, showing SifA-SKIP sequesters Rab9 to inhibit MPR transport.

   Evidence Reciprocal co-IP of the SifA-SKIP-Rab9 ternary complex in infected cells and RNAi of SKIP with MPR trafficking assay in uninfected cells

   PMID:23162002

   Open questions at the time

   • Mechanism by which SKIP normally engages Rab9 in uninfected cells not fully resolved
   • Relationship between retrograde and anterograde SKIP functions unclear
4. 2015 Medium

   Connected SKIP-mediated peripheral lysosome positioning to membrane tethering and cargo degradation by showing it recruits HOPS subunits.

   Evidence Co-IP of SKIP with HOPS subunits and RNAi of SKIP with EGFR degradation and lysosome trafficking readouts

   PMID:25908847

   Open questions at the time

   • Direct vs. bridged interaction with HOPS not defined
   • Single lab, no reciprocal structural validation
5. 2015 Medium

   Showed SKIP is a shared kinesin-1 adaptor across organelle types, acting as a Rab1A effector for anterograde melanosome transport distinct from ARL8-driven lysosome transport.

   Evidence Yeast two-hybrid and co-IP of Rab1A-SKIP, RNAi with melanosome distribution readout, and co-IP complex reconstitution

   PMID:25649263

   Open questions at the time

   • Whether Rab1A relieves SKIP autoinhibition like ARL8 not tested
   • Single lab
6. 2015 Medium

   Established human disease causality and the breadth of the trafficking defect, linking a PLEKHM2 frameshift mutation to perinuclear organelle collapse and impaired autophagy.

   Evidence Patient fibroblast organelle marker analysis, autophagy flux assay, and rescue by wild-type PLEKHM2 re-expression

   PMID:26464484

   Open questions at the time

   • Tissue-specific basis of cardiomyopathy not addressed in fibroblasts
   • Single family/lab
7. 2017 Medium

   Demonstrated a signaling-coupled function, showing TLR7-driven ARL8b activation uses SKIP to reposition lysosomes for type I interferon production.

   Evidence RNAi of SKIP and ARL8b in pDCs with TLR7 localization and IFN production readouts and live imaging

   PMID:29150602

   Open questions at the time

   • How TLR7 signaling activates ARL8b not defined
   • Single lab
8. 2019 High

   Identified a lipid-recognition function, showing SKIP binds PtdIns(4)P to drive lysosomal tubulation during phagolysosome resolution.

   Evidence Live imaging of SKIP/ARL8B recruitment, lipid-binding assays, and PtdIns(4)P depletion with resolution readouts

   PMID:31570833

   Open questions at the time

   • Which SKIP domain mediates phosphoinositide binding not pinpointed
   • Interplay between lipid binding and ARL8 recruitment unresolved
9. 2021 Medium

   Showed peripheral lysosome positioning by Plekhm2 is exploited by pathogens, since its depletion restores perinuclear lysosomes and bactericidal phagosome fusion against M. tuberculosis.

   Evidence RNAi of Plekhm2 in macrophages with lysosome positioning, lysosome-phagosome fusion, and bacterial survival assays

   PMID:33619301

   Open questions at the time

   • Whether the bacterium directly manipulates the ARL8-SKIP axis not shown
   • Single lab
10. 2020 High

    Defined the autoinhibition switch, showing the C-terminal PH domains fold onto the N-terminal motor-binding region and ARL8 relieves this inhibition while self-association boosts kinesin binding.

    Evidence Structure-function mutagenesis of SKIP domains, co-IP of N- and C-terminal fragments, and lysosome distribution and kinesin-1 interaction assays

    PMID:33232665

    Open questions at the time

    • No high-resolution structure of the autoinhibited or activated state
    • Quantitative thermodynamics of the switch not determined
11. 2022 Medium

    Extended SKIP's motor repertoire to kinesin-3, showing it recruits and activates KIF1Bβ on lysosomes and that SifA mimics this pathway.

    Evidence Co-IP of SKIP with KIF1Bβ, RNAi with lysosomal kinesin-3 localization readout, and bacterial vacuole stability assays

    PMID:34878110

    Open questions at the time

    • What determines kinesin-1 vs kinesin-3 selection on a given lysosome unknown
    • Direct vs bridged SKIP-KIF1Bβ contact not resolved
12. 2024 Medium

    Linked PLEKHM2 loss to cardiac pathology mechanistically, showing impaired autophagic flux causes mitochondrial damage, ROS, and reduced contractility in cardiomyocytes.

    Evidence PLEKHM2-KO hiPSC-cardiomyocytes with autophagic flux, mitochondrial ROS and membrane potential, contractility assays, and wild-type rescue

    PMID:38490981

    Open questions at the time

    • Whether the defect is primary to cardiomyocytes or secondary to other cell types unresolved
    • Mechanism linking lysosome mispositioning to mitophagy not detailed
13. 2024 Medium

    Showed cell-type specificity of PLEKHM2's autophagic role in vivo, with deficiency impairing autophagy in cardiofibroblasts but not cardiomyocytes in mice.

    Evidence Global Plekhm2 KO mouse with LC3II immunoblot, AKT phosphorylation, fasting challenge, cell-type-specific autophagy assays, and angiotensin-II hypertrophy model

    PMID:38942823

    Open questions at the time

    • Apparent discrepancy with hiPSC-cardiomyocyte data not reconciled
    • No overt cardiac dysfunction in young mice leaves disease mechanism open
14. 2025 High

    Uncovered a second mode of activation, showing a conserved +1 ribosomal frameshift makes a constitutively active SKIP proteoform that relieves autoinhibition independent of ARL8.

    Evidence Ribosome profiling, phylogenetic conservation, structure-function mutagenesis, localization imaging, and KO-cardiomyocyte contractility rescue with canonical vs frameshifted protein

    PMID:41134891

    Open questions at the time

    • What regulates the frequency of frameshifting in different cells unknown
    • Stoichiometry of the two proteoforms in vivo not quantified

• How the multiple SKIP regulatory inputs — ARL8/Rab1A recruitment, autoinhibition relief, phosphoinositide binding, frameshift proteoform balance, and motor selection — are integrated to specify organelle-, cell-type-, and signal-specific transport remains unresolved.
• No high-resolution structure of activated SKIP-motor complexes
• Determinants of kinesin-1 vs kinesin-3 vs Rab1A vs ARL8 usage undefined
• Mechanistic basis of the cardiomyopathy phenotype not fully established