PIP4P1

PIP4P1 (TMEM55B) is an integral lysosomal membrane protein that functions as a central adaptor-recruitment hub coordinating lysosomal positioning, signaling, repair, and autophagic flux. Its cytosolic region comprises two tandem Zn²⁺-stabilized RING-like β-sandwich domains that engage a conserved TMEM55B-binding motif (TBM) present in multiple effectors—including JIP4, JIP3, RILPL1, OCRL, WDR81, and TBC1D9B—thereby recruiting dynein for retrograde lysosomal transport, facilitating TBC1D9B-mediated ARL8B GTPase inactivation, promoting ESCRT-dependent lysosomal repair, sequestering FLCN/FNIP to activate TFE3, and mediating NEDD4-dependent ubiquitination of PLEKHM1 and cystinosin (PMID:29146937, PMID:41314214, PMID:41832156, PMID:38168055). Lysosomal targeting requires S-palmitoylation and a dileucine sorting motif, and its activity is positively regulated by Erk/MAPK phosphorylation at Ser76/Ser169, which enhances perinuclear lysosomal clustering (PMID:34350967, PMID:31329883). PIP4P1 also contributes to V-ATPase/Ragulator-dependent mTORC1 activation in response to amino acids (PMID:29644770).

1. 2017 High

   Identifying how lysosomes achieve regulated retrograde transport, this study established that TMEM55B recruits the dynein adaptor JIP4 to lysosomes, providing the first defined molecular function for this lysosomal membrane protein.

   Evidence Overexpression/shRNA knockdown with LAMP1 imaging, Co-IP, and dynein inhibition in mammalian cells

   PMID:29146937

   Open questions at the time

   • Structural basis of JIP4 recruitment unknown
   • Whether TMEM55B acts as a general adaptor platform not yet explored
   • Regulatory inputs controlling TMEM55B–JIP4 interaction undefined
2. 2018 Medium

   Addressing whether TMEM55B participates in lysosomal nutrient signaling beyond positioning, this work showed TMEM55B interacts with V-ATPase and Ragulator components and is required for amino acid–induced mTORC1 activation.

   Evidence Proteomics, Co-IP, lipid raft fractionation, and siRNA knockdown with S6K/4E-BP phosphorylation readouts

   PMID:29644770

   Open questions at the time

   • Direct versus indirect role in V-ATPase assembly not resolved
   • Relationship between mTORC1 activation and lysosomal positioning functions unclear
   • Single-lab observation
3. 2019 Medium

   Revealing how signaling pathways regulate lysosomal positioning via TMEM55B, Erk/MAPK-mediated phosphorylation at Ser76 and Ser169 was shown to promote perinuclear lysosomal clustering without affecting intrinsic phosphatase activity.

   Evidence MEK1/2 inhibition, phospho-site mutagenesis, CRISPR knockout, and LAMP1 imaging

   PMID:31329883

   Open questions at the time

   • Downstream molecular consequence of phosphorylation (e.g., enhanced JIP4 binding) not tested
   • In vivo relevance of Erk-dependent regulation not established
   • Other kinases that target TMEM55B not explored
4. 2021 High

   Resolving how TMEM55B reaches its functional site, S-palmitoylation at multiple cysteines and a dileucine sorting motif were shown to be jointly required for lysosomal targeting; loss of palmitoylation traps TMEM55B in the Golgi and abolishes lysosomal clustering.

   Evidence Cysteine mutagenesis, palmitoylation assay, subcellular fractionation, and LAMP1 clustering assay

   PMID:34350967

   Open questions at the time

   • Identity of the palmitoyl acyltransferase(s) unknown
   • Whether palmitoylation is dynamically regulated not tested
   • Role of individual cysteine sites not deconvolved
5. 2023 High

   Connecting TMEM55B to Parkinson's-relevant lysosomal biology, RILPL1—recruited by LRRK2-phosphorylated Rab proteins—was found to bind TMEM55B at lysosomes, with TMEM55B knockout increasing RILPL1 protein levels, suggesting TMEM55B-dependent turnover.

   Evidence Quantitative proteomics, Co-IP, LRRK2 inhibitor and proteasome inhibitor treatments, knockout mouse fibroblasts

   PMID:38091401

   Open questions at the time

   • Whether TMEM55B directly mediates RILPL1 degradation or indirectly regulates it not resolved
   • Functional consequence of TMEM55B–RILPL1 interaction on lysosomal motility not determined
   • Structural basis of the interaction unknown at this point
6. 2024 High

   Expanding TMEM55B's role to stress-responsive lysosomal quality control, this study showed TMEM55B mediates NEDD4-dependent ubiquitination and degradation of PLEKHM1, recruits ESCRT machinery for lysosomal repair, and sequesters FLCN/FNIP to promote TFE3 nuclear translocation under oxidative stress.

   Evidence Co-IP, ubiquitination assays, proteasome inhibition, ESCRT imaging, FLCN/FNIP pulldown, TFE3 localization, tmem55 knockout zebrafish

   PMID:38168055

   Open questions at the time

   • How TMEM55B selects between its multiple adaptor partners under different stresses is unknown
   • Whether NEDD4 is recruited directly by TMEM55B or via an intermediary not fully resolved
   • Relative importance of PLEKHM1 degradation vs. ESCRT recruitment for autophagic flux unclear
7. 2025 High

   Providing the structural basis for TMEM55B's hub function, crystal structures revealed tandem RING-like Zn²⁺-stabilized β-sandwich domains that engage a conserved TBM via backbone hydrogen bonding; proteomics confirmed six TBM-containing partners (JIP3, JIP4, RILPL1, OCRL, WDR81, TBC1D9B), unifying prior interaction observations.

   Evidence X-ray crystallography, Co-IP, mass spectrometry, site-directed mutagenesis

   PMID:41314214

   Open questions at the time

   • Structure of the full-length transmembrane protein not determined
   • Whether multiple TBM partners bind simultaneously or compete for the same site not resolved
   • Allosteric regulation of TBM binding by phosphorylation or palmitoylation not examined structurally
8. 2026 High

   Establishing a direct link between TMEM55B and small GTPase regulation, TBC1D9B was shown to be recruited by TMEM55B to lysosomes where it acts as a GAP for ARL8B; TMEM55B knockout phenocopied ARL8 hyperactivation with lysosomal dispersion and defective autophagic flux, effects epistatic with ARL8 depletion.

   Evidence Co-IP, in vitro GTPase assay, knockout cell lines, LAMP1 imaging, autophagic flux assay, double-knockout epistasis

   PMID:41832156

   Open questions at the time

   • Whether TMEM55B–TBC1D9B–ARL8B axis operates at all lysosomes or a subpopulation not known
   • Integration with JIP4-dynein pathway at the mechanistic level not delineated
   • In vivo physiological consequence of disrupting this axis not tested in mammals

• Key unresolved questions include how TMEM55B coordinates simultaneous or sequential binding of its multiple TBM-containing partners, whether competition among adaptors encodes context-dependent lysosomal fate decisions, and what the full-length transmembrane structure and dynamics look like.
• No full-length structure or cryo-EM model available
• Mechanism of partner selectivity under specific cellular stresses undefined
• No genetic disease directly linked to PIP4P1 mutations in human studies