PIP4P1

PIP4P1 (TMEM55B) is an integral lysosomal membrane protein that serves as a central scaffolding hub coordinating lysosomal positioning, stress responses, and degradative flux (PMID:29146937, PMID:41314214). Its cytosolic region folds into two tandem RING-like domains, each a Zn2+-stabilized β-sandwich, that engage adaptor proteins through a shallow groove recognizing a conserved TMEM55B-binding motif (TBM); through this interface it recruits multiple clients including JIP3, JIP4, OCRL, WDR81, TBC1D9B, and RILPL1 (PMID:41314214). By recruiting JIP4 to the lysosomal surface, TMEM55B drives dynein-dependent retrograde transport toward the microtubule minus-end, producing perinuclear lysosome clustering, while its loss disperses lysosomes to the cell periphery (PMID:29146937). This positioning activity is regulated transcriptionally—TFEB and TFE3 upregulate TMEM55B upon starvation or lysosomal stress, and TMEM55B-driven retrograde transport is required for autophagosome–lysosome fusion (PMID:29146937). TMEM55B also constrains lysosome dispersion via TBC1D9B, a GAP that stimulates the GTPase activity of ARL8B, with TMEM55B loss-of-function phenotypes occluded by ARL8 co-depletion (PMID:41832156). Beyond positioning, TMEM55B participates in mTORC1 signaling through interactions with V-ATPase and Ragulator components (PMID:29644770), in oxidative-stress responses by promoting NEDD4-dependent ubiquitination of PLEKHM1 to halt fusion and by recruiting ESCRT machinery for lysosomal repair (PMID:38168055), and in transcriptional stress signaling by sequestering the FLCN/FNIP complex to enable TFE3 nuclear translocation (PMID:38168055). The protein's lysosomal delivery depends on S-palmitoylation of cytoplasmic cysteines together with a dileucine sorting motif, and its lysosome-clustering activity is tuned by Erk/MAPK phosphorylation at Ser76 and Ser169 (PMID:31329883, PMID:34350967). A zebrafish tmem55 knockout shows increased susceptibility to oxidative stress, establishing an in vivo requirement (PMID:38168055).

1. 2017 High

   Established TMEM55B as a lysosomal positioning factor by showing it recruits JIP4 to drive dynein-dependent retrograde transport, defining the first molecular function of the protein.

   Evidence Overexpression, shRNA depletion, live imaging of lysosome positioning, and Co-IP in cultured cells

   PMID:29146937

   Open questions at the time

   • Did not resolve how TMEM55B physically links to dynein machinery beyond JIP4
   • Did not define the structural basis of the JIP4 interaction
2. 2017 High

   Placed TMEM55B in a stress-responsive transcriptional circuit by showing TFEB/TFE3 upregulate it during starvation and that it is required for starvation-induced retrograde transport and autophagosome–lysosome fusion.

   Evidence Reporter assays, qRT-PCR, TFEB/TFE3 overexpression, shRNA depletion, immunofluorescence

   PMID:29146937

   Open questions at the time

   • Did not establish whether the transcriptional regulation forms a closed feedback loop
   • Did not separate fusion defects from positioning defects mechanistically
3. 2018 Medium

   Connected TMEM55B to nutrient signaling by linking it to V-ATPase/Ragulator assembly and amino acid-induced mTORC1 substrate phosphorylation, and identified a feedback relationship with TFEB.

   Evidence Proteomics, Co-IP, lipid raft fractionation, immunoblot for S6K/4E-BP1, and TFEB localization by IF after KD

   PMID:29644770

   Open questions at the time

   • Single-lab study without orthogonal confirmation of the V-ATPase interaction
   • Direct versus indirect contribution to mTORC1 activation not dissected
   • TFEB feedback shown only by localization
4. 2019 High

   Showed that TMEM55B activity is regulated post-translationally by Erk/MAPK phosphorylation at Ser76/Ser169 downstream of TLR signaling, modulating lysosome clustering independently of intrinsic phosphatase activity.

   Evidence Phosphosite mutagenesis, MEK1/2 inhibitor (U0126), shRNA/CRISPR KO, LAMP1 IF, immunoblot

   PMID:31329883

   Open questions at the time

   • Mechanism by which phosphorylation alters clustering not defined
   • Functional link between TLR signaling and lysosome positioning physiology not established
5. 2021 High

   Defined the trafficking determinants of TMEM55B, demonstrating that S-palmitoylation of cytoplasmic cysteines plus a dileucine motif route the protein to lysosomes and are required for its clustering activity.

   Evidence Acyl-RAC palmitoylation assay, cysteine and dileucine mutagenesis, IF, subcellular fractionation

   PMID:34350967

   Open questions at the time

   • The palmitoyltransferase responsible was not identified
   • Whether palmitoylation is dynamically regulated was not addressed
6. 2023 High

   Linked TMEM55B to Parkinson's disease pathways by showing VPS35[D620N]/LRRK2-driven phospho-Rab signaling recruits RILPL1 to lysosomes where it binds TMEM55B directly, and that TMEM55B regulates RILPL1 levels.

   Evidence Co-IP, mass spectrometry, mutagenesis, KO mouse tissues, LRRK2 and proteasome inhibitor treatment

   PMID:38091401

   Open questions at the time

   • Functional consequence of the RILPL1–TMEM55B interaction for disease not resolved
   • Did not determine whether RILPL1 binds the same site as JIP4
7. 2024 High

   Established TMEM55B as a master regulator of the oxidative-stress lysosomal response, coordinating NEDD4-dependent PLEKHM1 degradation to halt fusion, ESCRT-mediated repair, FLCN/FNIP sequestration for TFE3 activation, and an in vivo oxidative-stress requirement.

   Evidence Co-IP, ubiquitination assays, ESCRT recruitment IF, TFE3 localization, KO cells, lysosomal damage assays, zebrafish tmem55 KO arsenite survival

   PMID:38168055

   Open questions at the time

   • How a single protein switches between these distinct outputs not resolved
   • ESCRT and FLCN/FNIP arms rest on single-lab Co-IP plus KO without reciprocal validation
   • Direct versus indirect role in PLEKHM1 ubiquitination not fully separated
8. 2025 High

   Provided the structural basis for hub function, solving crystal structures of the cytosolic tandem RING-like domains and a RILPL1 TBM complex, and identifying a shared set of TBM-bearing adaptors (JIP3, JIP4, OCRL, WDR81, TBC1D9B).

   Evidence X-ray crystallography of apo and complex forms, Co-IP, mass spectrometry, TBM mutagenesis

   PMID:41314214

   Open questions at the time

   • Did not determine whether adaptors compete for a single groove or bind simultaneously
   • Functional hierarchy among clients not established
9. 2026 High

   Resolved how TMEM55B antagonizes lysosome dispersion mechanistically by recruiting the GAP TBC1D9B to stimulate ARL8B GTPase activity, with epistasis showing TMEM55B acts through ARL8.

   Evidence Co-IP, GTPase activity assay, KO cells, ARL8/TMEM55B double-KO epistasis, IF

   PMID:41832156

   Open questions at the time

   • Spatiotemporal coordination between this GAP-based control and JIP4-dynein transport not defined
10. 2025 Medium

    Extended TMEM55B function into lysosomal metabolite homeostasis and membrane contact sites, implicating it in CTNS/cystine regulation via ubiquitylation and in ER–lysosome lipid and Ca2+ coordination via PDZD8.

    Evidence Ubiquitylation assays, JIP4 KO cells/mice, cystine measurement (preprint); PDZD8 Co-IP, lysosomal pH, lipid droplet and Ca2+ imaging (preprint)

    PMID:bio_10.1101_2025.06.06.657909 PMID:bio_10.1101_2025.10.21.683636

    Open questions at the time

    • Both findings are preprints not yet peer-reviewed
    • Whether TMEM55B is the direct E3-recruiting factor for CTNS not established
    • PDZD8 interaction not validated reciprocally

• It remains unknown how TMEM55B integrates and prioritizes its competing adaptor-driven outputs—positioning, repair, transcriptional stress, and metabolite control—at a single shared binding groove within an intact cell.
• No quantitative model of adaptor competition or hierarchy
• No structural data on multivalent or simultaneous client engagement
• Physiological triggers selecting each output are undefined