RILPL2

RILPL2 is a phospho-specific effector that couples LRRK2-phosphorylated Rab GTPases to cytoskeletal motors and ciliary regulation (PMID:32017888, PMID:33727250). Its RH2 domain assembles a heterotetramer with phospho-Rab8a (pT72) in which a RILPL2 α-helical dimer bridges two phospho-Rab molecules and an N-terminal X-cap orients arginine residues toward the phosphorylated threonine, providing the structural basis for selective recognition of LRRK2-phosphorylated Rabs (PMID:32017888). Through this axis, phospho-Rab10 co-recruits RILPL2 and Myosin Va to the peri-centriolar region and retains the motor over pericentriolar membranes, blocking ciliogenesis; RILPL2 overexpression suffices to suppress ciliogenesis in RPE cells (PMID:33727250). RILPL2 localizes dynamically to the primary cilium and centrosome and promotes removal of signaling proteins from the ciliary membrane to control its composition (PMID:23264467). Independently of the ciliary axis, RILPL2 binds the globular tail domain of Myosin Va and, together with melanophilin and the binding partner Rab36, activates Myosin Va motor function (PMID:31175157), and acts downstream of Myosin Va in a Rac1–PAK pathway driving dendritic spine morphogenesis (PMID:19812310). A more recent activity links RILPL2 to metabolic control, where it recruits the E3 ligase TRIM21 to drive K48-linked ubiquitination and degradation of LDHA, suppressing glycolytic reprogramming (PMID:42082464).

1. 2009 High

   Established RILPL2 as a Myosin Va interactor that drives dendritic spine morphogenesis, defining its first functional role downstream of a motor protein in Rac1-PAK signaling.

   Evidence Reciprocal Co-IP, shRNA knockdown with rescue, and epistasis via dominant-negative MyoVa tail in hippocampal neurons

   PMID:19812310

   Open questions at the time

   • Direct interaction interface on Myosin Va not mapped
   • How RILPL2 links MyoVa to Rac1/PAK activation mechanistically unresolved
2. 2012 Medium

   Identified RILPL2 as a ciliary/centrosomal protein that limits ciliary membrane protein concentration, framing its role in cilium homeostasis.

   Evidence Live-cell microscopy, shRNA depletion (with RILPL1), and 3D epithelial organization assay

   PMID:23264467

   Open questions at the time

   • RILPL1 and RILPL2 were co-depleted, limiting gene-specific attribution
   • Mechanism of ciliary protein removal not defined
3. 2019 High

   Reconstituted RILPL2 as a co-activator of Myosin Va motor function with melanophilin, with Rab36 stimulating the RILPL2–GTD interaction to expose the Mlph-binding site.

   Evidence In vitro ATPase and single-molecule motility assays, GST pulldown, analytical ultracentrifugation

   PMID:31175157

   Open questions at the time

   • Cellular context where Rab36-dependent activation operates not established
   • Relationship to the Rac1-PAK spine pathway unclear
4. 2019 Low

   Proposed a tumor-suppressive role via RILPL2–TUBB3 destabilization and PTEN/AKT regulation, extending RILPL2 function to cancer cell behavior.

   Evidence Co-IP, overexpression in breast cancer models, PTEN/AKT pathway analysis

   PMID:31497344

   Open questions at the time

   • Single Co-IP without mutagenesis or reconstitution
   • Direct versus indirect TUBB3 destabilization undefined
   • Not independently confirmed
5. 2020 High

   Solved the structural basis for phospho-Rab recognition, showing the RH2 X-cap reads the LRRK2-phosphorylated threonine to define RILPL2 as a phospho-specific effector.

   Evidence X-ray crystallography of pRab8a–RILPL2 RH2 complex with X-cap residue analysis

   PMID:32017888

   Open questions at the time

   • Downstream consequences of the heterotetramer in cells not addressed in this structural study
   • Selectivity across the full phospho-Rab repertoire not fully resolved
6. 2021 High

   Connected phospho-Rab effector function to ciliogenesis, showing phospho-Rab10 co-recruits RILPL2 and Myosin Va to pericentriolar membranes to block cilium formation.

   Evidence Co-IP, FLIP microscopy, and phosphoRab10-dependent relocalization in RPE cells with pathogenic LRRK2

   PMID:33727250

   Open questions at the time

   • Without pathogenic LRRK2, RILPL2 is not essential for ciliogenesis, leaving its baseline role open
   • How motor retention mechanistically prevents cilium assembly not detailed
7. 2026 Medium

   Revealed a metabolic-regulatory function in which RILPL2 recruits TRIM21 to ubiquitinate and degrade LDHA, suppressing glycolytic reprogramming.

   Evidence Co-IP, K48-linkage ubiquitination assay, protein stability assay, and H3K18 lactylation measurement in cervical cancer cells

   PMID:42082464

   Open questions at the time

   • No mutagenesis or reconstitution defining the RILPL2–TRIM21–LDHA interface
   • Whether this activity connects to the phospho-Rab or motor functions is unknown

• How RILPL2's distinct activities — phospho-Rab effector at the cilium, Myosin Va co-activator, and TRIM21 adaptor for LDHA degradation — are integrated or context-selected within a single cell remains unresolved.
• No unifying model linking the cytoskeletal, ciliary, and metabolic roles
• Physiological versus pathogenic-LRRK2 contexts not disentangled