id: MODULE:chaperone_mediated_autophagy title: Chaperone-mediated autophagy (HSPA8 substrate delivery and LAMP-2A translocation) description: >- Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway for soluble cytosolic proteins that carry a KFERQ-like pentapeptide motif. The constitutive Hsp70 chaperone HSPA8/Hsc70 recognizes the motif in the cytosol and delivers the substrate to the cytosolic side of the lysosomal membrane, where it binds monomeric LAMP-2A, the CMA-specific splice isoform of LAMP2. Substrate binding drives LAMP-2A multimerization into a high-molecular-weight translocation complex, the unfolded substrate crosses the membrane, and it is degraded by lumenal hydrolases; HSPA8 then disassembles the LAMP-2A complex, returning LAMP-2A to its monomeric, substrate-binding state. The module covers substrate recognition and delivery, translocation through the LAMP-2A complex, and complex recycling. Regulation of CMA (for example lysosomal mTORC2/PHLPP1/AKT signalling or cathepsin A-mediated LAMP-2A turnover), the cochaperones that assist HSPA8 at the membrane, and the downstream consequences of degrading particular substrates (NLRP3, BBC3/PUMA, GPX4) are outside the boundary. status: DRAFT scope: ABSTRACT evidence: - source_id: PMID:2799391 title: A role for a 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins. statement: An Hsp70-family protein binds the lysosomal targeting peptide regions and enhances lysosomal proteolysis. supporting_text: >- A 73-kilodalton (kD) intracellular protein was found to bind to peptide regions that target intracellular proteins for lysosomal degradation in response to serum withdrawal. - source_id: PMID:18644871 title: The chaperone-mediated autophagy receptor organizes in dynamic protein complexes at the lysosomal membrane. statement: Substrates bind monomeric LAMP-2A, and translocation requires a high-molecular-weight LAMP-2A complex whose disassembly depends on hsc70. supporting_text: >- Substrate proteins only bind to monomeric LAMP-2A, while the efficient translocation of substrates requires the formation of a particular high-molecular-weight LAMP-2A complex. notes: >- Built as the decomposition target for the precomposed GO:0061740 "protein targeting to lysosome involved in chaperone-mediated autophagy" (projects/INVOLVED_IN_PRECOMPOSITION.md): the delivery step is GO:0006622 protein targeting to lysosome as part of GO:0061684 chaperone-mediated autophagy. Human proteins are representative members (HSPA8 P11142, reviewed in genes/human/HSPA8; LAMP2 P13473, isoform LAMP-2A P13473-1 per UniProt, no gene review yet). The HSPA8 annoton function, protein-macromolecule adaptor activity, matches both the HSPA8 core function and the HSPA8 activity in production GO-CAM gomodel:63c0ac2b00001252. That model types the LAMP2 activity as signaling adaptor activity (GO:0035591), which describes a signal relay rather than substrate binding and translocation. The cited data show LAMP-2A binds the substrate and that its multimerization is required for translocation, but not whether LAMP-2A itself forms the conduit. Neither transmembrane protein transporter activity (the conduit claim) nor cargo receptor activity (defined for delivery to transport vesicles) is established, so the LAMP-2A function carries no GO id, only a preferred term. No PANTHER family ids are asserted. module: id: chaperone_mediated_autophagy label: chaperone-mediated autophagy module_type: BIOLOGICAL_PROCESS concepts: - preferred_term: chaperone-mediated autophagy term: id: GO:0061684 label: chaperone-mediated autophagy description: Selective, receptor-mediated translocation of KFERQ-motif cytosolic proteins into lysosomes for degradation. context: taxa: - preferred_term: mammals term: id: NCBITaxon:40674 label: Mammalia description: LAMP-2A, the CMA receptor isoform, is characterized in mammals; human proteins are the representative members. gocam_associations: - model: gomodel:63c0ac2b00001252 title: Palmitoylation of NLRP3 by ZDHHC12, leading to NLRP3 degradation by the chaperone-mediated autophagy pathway (Human) notes: Production model containing HSPA8 substrate delivery (protein targeting to lysosome involved in CMA) and LAMP2 (chaperone-mediated autophagy) for the substrate NLRP3. parts: - order: 1 role: KFERQ-substrate recognition and delivery to the lysosome node: id: cma_substrate_delivery label: HSPA8 delivery of KFERQ-motif substrates to the lysosomal membrane module_type: TRANSPORT_STEP description: >- Cytosolic HSPA8/Hsc70 binds the KFERQ-like motif of a substrate protein and brings it to the cytosolic face of the lysosomal membrane, where HSPA8 associates with cochaperones and presents the substrate to LAMP-2A. gocam_associations: - model: gomodel:63c0ac2b00001252 activity: gomodel:63c0ac2b00001252/63c0ac2b00001260 title: HSPA8 protein-macromolecule adaptor activity (NLRP3 delivery) annotons: - id: hspa8_substrate_adaptor label: HSPA8/Hsc70 substrate-recognition chaperone participant: selector_type: GENE_PRODUCT gene_product: preferred_term: HSPA8 (human) term: id: UniProtKB:P11142 label: Heat shock cognate 71 kDa protein function: preferred_term: protein-macromolecule adaptor activity term: id: GO:0030674 label: protein-macromolecule adaptor activity evidence: - source_id: PMID:11559757 statement: Hsc70 on the cytosolic side of the lysosomal membrane binds CMA substrates and is required for their transport into lysosomes. supporting_text: >- is associated with the cytosolic side of the lysosomal membrane where it binds to substrates of this proteolytic pathway - source_id: PMID:26212789 statement: BBC3/PUMA associates with HSPA8 and is delivered to lysosomes by CMA. supporting_text: >- BBC3 associates with HSPA8/HSC70 (heat shock 70kDa protein 8), leading to its lysosome translocation and uptake. processes: - preferred_term: protein targeting to lysosome term: id: GO:0006622 label: protein targeting to lysosome locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: Recognizes the KFERQ-like motif of a cytosolic substrate and delivers it to LAMP-2A at the lysosomal membrane. - order: 2 role: Translocation through the LAMP-2A complex and its recycling node: id: cma_lamp2a_translocation label: LAMP-2A multimerization, substrate translocation and complex disassembly module_type: TRANSPORT_STEP description: >- Substrate binds monomeric LAMP-2A at the lysosomal membrane; LAMP-2A assembles into a high-molecular-weight translocation complex through which the unfolded substrate enters the lumen. HSPA8 then disassembles the complex, returning LAMP-2A to substrate-binding monomers. concepts: - preferred_term: chaperone-mediated autophagy translocation complex term: id: GO:0061742 label: chaperone-mediated autophagy translocation complex annotons: - id: lamp2a_translocation label: LAMP-2A CMA receptor participant: selector_type: GENE_PRODUCT gene_product: preferred_term: LAMP2 (human, isoform LAMP-2A) term: id: UniProtKB:P13473 label: Lysosome-associated membrane glycoprotein 2 function: preferred_term: CMA substrate receptor (binds substrate; multimerizes for translocation) evidence: - source_id: PMID:18644871 statement: Substrates bind monomeric LAMP-2A and translocation requires its high-molecular-weight complex. supporting_text: >- Substrate proteins bind to the lysosomal membrane through the lysosome-associated membrane protein type 2A (LAMP-2A) processes: - preferred_term: chaperone-mediated autophagy term: id: GO:0061684 label: chaperone-mediated autophagy locations: - preferred_term: lysosomal membrane term: id: GO:0005765 label: lysosomal membrane role_description: Binds the delivered substrate as a monomer and, as a multimeric complex, is required for its translocation into the lysosomal lumen. - id: hspa8_complex_disassembly label: HSPA8 disassembly of the LAMP-2A complex participant: selector_type: GENE_PRODUCT gene_product: preferred_term: HSPA8 (human) term: id: UniProtKB:P11142 label: Heat shock cognate 71 kDa protein function: preferred_term: ATP-dependent protein folding chaperone term: id: GO:0140662 label: ATP-dependent protein folding chaperone evidence: - source_id: PMID:18644871 statement: hsc70 disassembles LAMP-2A from its complexes. supporting_text: >- we have identified a novel function for hsc70 in the disassembly of LAMP-2A from these complexes processes: - preferred_term: chaperone-mediated autophagy translocation complex disassembly term: id: GO:1904764 label: chaperone-mediated autophagy translocation complex disassembly locations: - preferred_term: lysosomal membrane term: id: GO:0005765 label: lysosomal membrane role_description: Releases LAMP-2A from the translocation complex after substrate uptake, resetting the receptor. connections: - source: cma_substrate_delivery target: cma_lamp2a_translocation connection_type: PROVIDES_INPUT_FOR description: HSPA8 delivers the KFERQ-motif substrate to monomeric LAMP-2A at the lysosomal membrane.