Dataset Information

SLC15A4 (PHT1) interaction proteomics

ABSTRACT: Human genetics and mouse models provide compelling evidence for the involvement of SLC15A4 in endosomal TLR activation. To gain an understanding of the molecular mechanism, we set out to identify its binding partners by interaction proteomics. TAP-MS/MS analysis of different SLC15A4 protein variants provided a global view of the SLC15A4 interaction landscape. Among the proteins detected, the uncharacterized protein CXorf21 emerged as a prominent and specific binder. CXorf21 is a X chromosome-encoded gene which has also been linked to SLE by a GWAS. CXorf21 was robustly identified with all the SLC15A4 constructs tested, indicating that the interaction does not require the N-terminal or central cytoplasmic region of the transporter. Reciprocal TAP-MS/MS analysis using tagged CXorf21 identified endogenous SLC15A4 as a specific interactor.

INSTRUMENT(S): LTQ Orbitrap Velos, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Thp-1 Cell, Monocyte

SUBMITTER: Ulrich Goldmann

LAB HEAD: Giulio Superti-Furga

PROVIDER: PXD014254 | Pride | 2020-05-14

REPOSITORIES: Pride

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Publications

TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9.

Heinz Leonhard X LX Lee JangEun J Kapoor Utkarsh U Kartnig Felix F Sedlyarov Vitaly V Papakostas Konstantinos K César-Razquin Adrian A Essletzbichler Patrick P Goldmann Ulrich U Stefanovic Adrijana A Bigenzahn Johannes W JW Scorzoni Stefania S Pizzagalli Mattia D MD Bensimon Ariel A Müller André C AC King F James FJ Li Jun J Girardi Enrico E Mbow M Lamine ML Whitehurst Charles E CE Rebsamen Manuele M Superti-Furga Giulio G

Nature 20200513 7808

Toll-like receptors (TLRs) have a crucial role in the recognition of pathogens and initiation of immune responses1-3. Here we show that a previously uncharacterized protein encoded by CXorf21-a gene that is associated with systemic lupus erythematosus4,5-interacts with the endolysosomal transporter SLC15A4, an essential but poorly understood component of the endolysosomal TLR machinery also linked to autoimmune disease4,6-9. Loss of this type-I-interferon-inducib ...[more]

PMID: 32433612

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Project description:L-3,4-dihydroxyphenylalanine (levodopa) treatment is the major pharmacotherapy for Parkinson's disease. However, almost all patients receiving levodopa eventually develop debilitating involuntary movements (dyskinesia). While it is known that striatal spiny projection neurons (SPNs) are involved in the genesis of this movement disorder, the molecular basis of dyskinesia is not understood. In this study, we identify distinct cell-type-specific gene expression changes that occur in sub-classes of SPNs upon induction of a parkinsonian lesion followed by chronic levodopa treatment. We identify several hundred genes whose expression is correlated with levodopa dose, many of which are under the control of AP-1 and ERK signaling. In spite of homeostatic adaptations involving several signaling modulators, AP-1-dependent gene expression remains highly dysregulated in direct pathway SPNs (dSPNs) upon chronic levodopa treatment. We also discuss which molecular pathways are most likely to dampen abnormal dopaminoceptive signaling in spiny projection neurons, hence providing potential targets for antidyskinetic treatments in Parkinson's disease. To profile the cell-type-specific responses of striatal spiny projection neurons (SPNs) to striatal dopamine depletion, we conducted TRAP analysis of the two major classes of these neurons: dSPNs that express the dopamine receptor 1a (Drd1a), and iSPNs that express the dopamine receptor 2 (Drd2). To disrupt dopamine innervation to both of these SPN populations that reside in the striatum, we injected the neurotoxin 6-hydroxydopamine (6-OHDA), unilaterally, in the medial forebrain bundle (MFB) in hemizygous Drd1-TRAP and Drd2-TRAP adult (9-14 weeks) male mice (kept on a C57BL/6J genetic background). This lesion procedure causes nigral dopamine cell death within a few days, along with a widespread and near-complete loss of dopaminergic innervation to the entire dorsal striatum on one side of the brain (a hemiparkinsonian model). We first examined the effects of dopamine depletion alone, compared to a mock lesion (ascorbate / saline injected). We then examined the effects of chronic levodopa treatment upon the molecular profiles of dopamine- depleted dSPNs and iSPNs, with two dose regimens. The ‘high-dose’ L-DOPA regimen (3 mg/kg on days 1-3, followed by 6 mg/kg on days 4-9) was expected to induce severe dyskinesia in all MFB-lesioned mice. The low-dose L-DOPA regimen (1 mg/kg on days 1-3, followed by 2 mg/kg on days 4-9) was expected to reverse limb use asymmetry without causing conspicuous dyskinesias. To equalize the effects of stress and handling across all groups, including control groups, all mice were equally handled and thus received saline injections when not receiving levodopa injections. Each treatment group contained 7-10 replicates. TRAP-purified mRNAs from either Drd1a- or Drd2-expressing SPNs were reverse-transcribed, amplified, and used to interrogate Affymetrix 430_2.0 GeneChip microarrays.

Dataset Information

SLC15A4 (PHT1) interaction proteomics

Publications

TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7-9.

Similar Datasets

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