| Functional role / biological process | Subcellular localization | Key molecular partners / effectors | Experimental evidence type | Notes / quantitative details | Key citation |
|---|---|---|---|---|---|
| Lysosome identity and positioning; major lysosomal small GTPase that drives lysosome dispersion to the cell periphery when active, while loss causes perinuclear/MTOC clustering | Cytosolic face of mature lysosomes; lysosome membrane; perinuclear vs peripheral lysosome pools | BORC (upstream recruiter), SKIP/PLEKHM2, kinesin machinery | RNAi/knockdown, overexpression, fluorescence microscopy, schematic/model synthesis | Microscopy scale bar 10 µm; Arl8a and Arl8b share ~91% identity; Arl8b overexpression disperses lysosomes whereas depletion clusters them near the MTOC (pqac-00000004, pqac-00000008, pqac-00000012) | Khatter et al. 2015. DOI: https://doi.org/10.1080/21592799.2015.1086501 |
| BORC-dependent recruitment of ARL8B to lysosomes upstream of anterograde transport | Lysosomal surface | BORC / BLOC-one-related complex; myrlysin/BORCS5 and other BORC subunits | CRISPR knockout, siRNA depletion, localization assays | BORC loss detaches Arl8b from lysosomes and phenocopies Arl8b depletion; BORC itself showed no detectable GEF activity toward Arl8b in the cited review summary (pqac-00000008) | Khatter et al. 2015. DOI: https://doi.org/10.1080/21592799.2015.1086501 |
| Coupling lysosomes to kinesin-1 for plus-end-directed anterograde motility | Peripheral lysosomes on microtubules | SKIP/PLEKHM2; kinesin-1 KIF5B/KLC | Affinity purification/binding, RNAi, overexpression, live/fixed-cell microscopy | SKIP binds kinesin light chain via WD motifs; KIF5B knockdown was >85% and caused central lysosome clustering similar to Arl8/SKIP depletion; mutation of SKIP WD residues (W207A/D208A/W236A/E237A) abolished KIF5B recruitment while preserving lysosome localization (pqac-00000009, pqac-00000014, pqac-00000015, pqac-00000016) | Rosa-Ferreira & Munro 2011. DOI: https://doi.org/10.1016/j.devcel.2011.10.007 |
| Activation mechanism of lysosome–kinesin coupling through SKIP | Lysosome membrane, ARL8-positive lysosomes | SKIP/PLEKHM2, kinesin-1 | Mechanistic cell biology / conformational model summarized in review evidence | ARL8 relieves SKIP autoinhibition to enable coupling of lysosomes to kinesin-1; establishes ARL8 as an active molecular switch rather than a passive lysosome marker (pqac-00000000, pqac-00000003) | Keren-Kaplan & Bonifacino 2021. DOI: https://doi.org/10.1016/j.cub.2020.10.071 |
| Recruitment and assembly of HOPS tethering complex for endosome–lysosome fusion and degradative trafficking | Lysosomal membranes; Arl8b- and hVps41-positive lysosomes | HOPS complex, VPS41 (hVps41), VPS39, SKIP/PLEKHM2 | RNAi depletion, rescue with WT vs binding-defective mutant, affinity purification, microscopy | Arl8b, but not Rab7, was required for hVps41 membrane localization; HOPS is hexameric and shares 4 of 6 core subunits with CORVET; EGFR degradation defect was rescued by WT hVps41 but not an Arl8b-binding-defective mutant (pqac-00000007) | Khatter et al. 2015. DOI: https://doi.org/10.1242/jcs.162651 |
| Coordination of lysosome motility and fusion through competitive effector binding | Late endosome–lysosome contact sites; lysosomes | PLEKHM1, Rab7, Arl8b, HOPS, SKIP/PLEKHM2 | Interaction mapping, domain analysis, cargo degradation assays, microscopy | PLEKHM1 simultaneously binds Rab7 and Arl8b; N-terminal RUN domain is necessary and sufficient for Arl8b interaction and lysosomal localization; PLEKHM1 RUN domain shares ~40% similarity with SKIP RUN domain and competes with SKIP for Arl8b binding, influencing lysosome positioning; Arl8a/b are ~91% identical (pqac-00000005) | Marwaha et al. 2017. DOI: https://doi.org/10.1083/jcb.201607085 |
| Retrograde lysosome trafficking and nutrient-dependent juxtanuclear repositioning | Peripheral lysosomes transitioning toward juxtanuclear lysosome pool | DENND6A, Rab34, RILP, dynein, Arl8b | GEF screening, BioID/proximity interactome, imaging, loss-of-function assays | DENND6A was identified as a potential GEF for ~20 Rabs including Rab34; Arl8b recruits DENND6A to peripheral lysosomes, DENND6A activates Rab34, and Rab34 recruits RILP/dynein to drive retrograde transport; DENND6A overexpression in assays was ~1.8× endogenous (pqac-00000001, pqac-00000002) | Kumar et al. 2024. DOI: https://doi.org/10.1038/s41467-024-44957-1 |
| Autophagy regulation through lysosome positioning and transport state | Lysosomes under nutrient-dependent spatial rearrangement | Arl8b, SKIP/PLEKHM2, HOPS, DENND6A-Rab34-RILP-dynein, mTORC1-linked lysosome positioning machinery | Knockdown/loss-of-function, trafficking assays, autophagic flux assays | Loss of DENND6A impaired autophagic flux; nutrient deprivation or altered lysosomal pH reduced lysosomal Arl8b/KIF2 and promoted perinuclear clustering with mTORC1 inactivation in review evidence; ARL8B thus integrates lysosome position with degradative signaling outputs (pqac-00000000, pqac-00000002, pqac-00000009) | Kumar et al. 2024. DOI: https://doi.org/10.1038/s41467-024-44957-1 |
| Neuronal/axonal lysosome transport relevance | Distal axon and peripheral neuronal lysosome compartments | BORC, Arl8b, SKIP, kinesins | Review synthesis of neuronal transport studies | ARL8/BORC pathway is placed on the anterograde/kinesin arm of axonal lysosome transport; disruptions in this pathway are linked broadly to neurological disease mechanisms (pqac-00000013) | Paumier & Gowrishankar 2024. DOI: https://doi.org/10.1016/j.ceb.2024.102382 |
| Human disease relevance through upstream BORC defects affecting ARL8-dependent lysosome dynamics | Lysosomes in human cells; distal axon / neuronal systems | BORCS8 (BORC subunit), ARL8, kinesin-1/-3 | Human genetics, cellular reconstitution, zebrafish knockout | Biallelic BORCS8 variants (p.Ser29Pro, p.Ser42Pro, p.Thr66Pro, p.Asn26Trpfs*51) reduced BORC assembly and impaired peripheral lysosome distribution; the frameshift allele was completely incapable of assembling with BORC or promoting peripheral lysosome distribution, linking BORC→ARL8 pathway failure to infantile-onset neurodegeneration (pqac-00000011) | De Pace et al. 2024. DOI: https://doi.org/10.1093/brain/awad427 |


*Table: This table summarizes experimentally supported functions, localization, effectors, evidence types, and quantitative notes for human ARL8B (UniProt Q9NVJ2). It is useful as a compact evidence map for lysosome positioning, motility, fusion, autophagy, and disease relevance.*