{"uniprot":"A6NCW7","gene":"USP17L4","name":"Inactive ubiquitin carboxyl-terminal hydrolase 17-like protein 4","organism":"Homo sapiens (Human)","status":"dark","length":530,"sequence":"MGDDSLYLGGEWQFNHFSKLTSSRPDAAFAEIQRTSLPEKSPLSSETRVDLCDDLAPVARQLAPREKLPLSSRRPAAVGAGLQNMGNTCYENASLQCLTYTLPLANYMLSREHSQTCQRPKCCMLCTMQAHITWALHSPGHVIQPSQALAAGFHRGKQEDVHEFLMFTVDAMKKACLPGHKQVDHHSKDTTLIHQIFGGCWRSQIKCLHCHGISDTFDPYLDIALDIQAAQSVKQALEQLVKPEELNGENAYHCGLCLQRAPASNTLTLHTSAKVLILVLKRFSDVAGNKLAKNVQYPECLDMQPYMSQQNTGPLVYVLYAVLVHAGWSCHDGYYFSYVKAQEGQWYKMDDAEVTVCSITSVLSQQAYVLFYIQKSEWERHSESVSRGREPRALGAEDTDRPATQGELKRDHPCLQVPELDEHLVERATEESTLDHWKFPQEQNKMKPEFNVRKVEGTLPPNVLVIHQSKYKCGMKNHHPEQQSSLLNLSSMNSTDQESMNTGTLASLQGRTRRSKGKNKHSKRSLLVCQ","function_summary":"A human cysteine-dependent deubiquitinating enzyme that removes ubiquitin from target proteins to sculpt signaling and chromatin-regulatory networks. By editing both degradative and nondegradative ubiquitin chains, it stabilizes and remodels complexes that govern innate immune sensing, MAPK and small GTPase pathways, cell-cycle transitions, apoptosis, and transcriptional control. It operates primarily in the cytosol and nucleus, with transient association at endoplasmic reticulum membranes where ubiquitin signaling coordinates trafficking and membrane targeting. Its mechanism relies on a papain-like catalytic core that confers precise ubiquitin-chain specificity and broad protein-binding capacity, enabling context-dependent regulation across cell proliferation, migration, and antiviral defense.","plain_language":"USP17L4 has barely been studied. The model's best guess: A human cysteine-dependent deubiquitinating enzyme that removes ubiquitin from target proteins to sculpt signaling and chromatin-regulatory networks. By editing both degradative and nondegradative ubiquitin chains, it stabilizes and remodels complexes that govern innate immune sensing, MAPK and small GTPase pathways, cell-cycle transitions, apoptosis, and transcriptional control.","uniprot_summary":"Deubiquitinating enzyme that removes conjugated ubiquitin from specific proteins to regulate different cellular processes.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"},{"id":"GO:0004843","label":"cysteine-type deubiquitinase activity"}],"biological_process":[{"id":"GO:0034260","label":"negative regulation of GTPase activity"},{"id":"GO:1901993","label":"regulation of meiotic cell cycle phase transition"},{"id":"GO:0040012","label":"regulation of locomotion"},{"id":"GO:0051051","label":"negative regulation of transport"},{"id":"GO:0048523","label":"negative regulation of cellular process"},{"id":"GO:0050778","label":"positive regulation of immune response"},{"id":"GO:0042127","label":"regulation of cell population proliferation"},{"id":"GO:0045089","label":"positive regulation of innate immune response"},{"id":"GO:0000165","label":"MAPK cascade"},{"id":"GO:0030334","label":"regulation of cell migration"},{"id":"GO:0010468","label":"regulation of gene expression"},{"id":"GO:0090317","label":"negative regulation of intracellular protein transport"},{"id":"GO:0043067","label":"regulation of programmed cell death"},{"id":"GO:1905476","label":"negative regulation of protein localization to membrane"},{"id":"GO:0010629","label":"negative regulation of gene expression"},{"id":"GO:0002699","label":"positive regulation of immune effector process"},{"id":"GO:0050688","label":"regulation of defense response to virus by host"},{"id":"GO:0050691","label":"regulation of defense response to virus by host"},{"id":"GO:0042981","label":"regulation of apoptotic process"},{"id":"GO:0051346","label":"negative regulation of hydrolase activity"},{"id":"GO:0039531","label":"regulation of viral-induced cytoplasmic pattern recognition receptor signaling pathway"},{"id":"GO:1902749","label":"regulation of cell cycle G2/M phase transition"},{"id":"GO:0051345","label":"positive regulation of hydrolase activity"},{"id":"GO:0043547","label":"positive regulation of GTPase activity"},{"id":"GO:0010955","label":"negative regulation of protein processing"},{"id":"GO:0039535","label":"regulation of RIG-I signaling pathway"},{"id":"GO:1900027","label":"regulation of ruffle assembly"},{"id":"GO:0051345","label":"positive regulation of hydrolase activity"},{"id":"GO:0090313","label":"negative regulation of protein targeting to membrane"},{"id":"GO:0071108","label":"protein K48-linked deubiquitination"},{"id":"GO:0031063","label":"regulation of histone deacetylation"},{"id":"GO:0070536","label":"protein K63-linked deubiquitination"}],"cellular_component":[{"id":"GO:0005829","label":"cytosol"},{"id":"GO:0016020","label":"membrane"},{"id":"GO:0005783","label":"endoplasmic reticulum"},{"id":"GO:0005789","label":"endoplasmic reticulum membrane"},{"id":"GO:0005634","label":"nucleus"}]},"interpro":[{"id":"IPR038765","name":"Papain-like cysteine peptidase superfamily","type":"homologous_superfamily","start":79,"end":387},{"id":"IPR001394","name":"Peptidase C19, ubiquitin carboxyl-terminal hydrolase","type":"domain","start":80,"end":372},{"id":"IPR028889","name":"Ubiquitin specific protease USP, catalytic domain","type":"domain","start":80,"end":375},{"id":"IPR050164","name":"Ubiquitin carboxyl-terminal hydrolases","type":"family","start":57,"end":376}],"reasoning":"I begin with the InterPro architecture. The core of the protein is a papain-like cysteine peptidase scaffold: IPR038765 (Papain-like cysteine peptidase superfamily, residues 79–387) provides the catalytic fold that supports thiol proteolysis. Nested within this scaffold are three USP-family signatures that define ubiquitin-directed specificity: IPR001394 (Peptidase C19, ubiquitin carboxyl-terminal hydrolase, residues 80–372), IPR028889 (Ubiquitin specific protease USP, catalytic domain, residues 80–375), and IPR050164 (Ubiquitin carboxyl-terminal hydrolases family, residues 57–376). The ordered overlap of these USP domains around the papain-like core establishes a cysteine-dependent deubiquitinase that recognizes and hydrolyzes isopeptide bonds at ubiquitin C-termini. This architecture causes cysteine-type deubiquitinase activity and necessitates broad protein binding to engage ubiquitin, substrates, and regulatory partners.\n\nFrom this catalytic foundation, I infer molecular function. The papain-like fold and USP catalytic domain directly encode GO:0004843 cysteine-type deubiquitinase activity. The extensive binding surfaces and regulatory roles require GO:0005515 protein binding to recruit substrates and cofactors. Together, these functions position the enzyme as a versatile DUB that edits ubiquitin signals.\n\nThis enzymatic activity propagates into diverse biological processes through targeted deubiquitination. By removing K48-linked chains (GO:0071108 protein K48-linked deubiquitination) and K63-linked chains (GO:0070536 protein K63-linked deubiquitination), the enzyme modulates proteasomal turnover and signaling scaffolds. Such editing explains broad regulatory outcomes: it tunes GO:0000165 MAPK cascade signaling; restrains or promotes small GTPase circuits, accounting for both GO:0034260 negative regulation of GTPase activity and GO:0043547 positive regulation of GTPase activity; and shapes cell behaviors captured by GO:0042127 regulation of cell population proliferation and GO:0030334 regulation of cell migration. Its control over chromatin-directed pathways and transcriptional regulators supports GO:0010468 regulation of gene expression and GO:0042981 regulation of apoptotic process. By stabilizing or remodeling complexes, it can both GO:0051346 negative regulation of hydrolase activity and GO:0051345 positive regulation of hydrolase activity, reflecting context-dependent pathway control.\n\nThe DUB’s influence extends to innate immunity and cell-cycle transitions. By removing inhibitory ubiquitin marks on cytosolic RNA sensors and their adaptors, it drives GO:0045089 positive regulation of innate immune response and GO:0039535 regulation of RIG-I signaling pathway, thereby enhancing antiviral defense (GO:0050691 regulation of defense response to virus by host). Its governance of ubiquitin-dependent checkpoints and assembly factors supports GO:1902749 regulation of cell cycle G2/M phase transition and GO:1901993 regulation of meiotic cell cycle phase transition. The enzyme’s capacity to gate trafficking and membrane-associated assemblies explains GO:0090317 negative regulation of intracellular protein transport and GO:0090313 negative regulation of protein targeting to membrane, while cytoskeletal remodeling nodes rationalize GO:1900027 regulation of ruffle assembly.\n\nCellular localization follows from function and binding requirements. The soluble catalytic core and broad regulatory interactions place the enzyme in the GO:0005829 cytosol. Its roles in transcriptional and chromatin-linked pathways, together with nuclear shuttling signals typical of USPs, support presence in the GO:0005634 nucleus. Association with membrane-proximal signaling and secretory checkpoints explains transient residence at the GO:0005789 endoplasmic reticulum membrane, where ubiquitin editing coordinates ER-associated processes.\n\nMechanistically, the enzyme likely recognizes K48- and K63-linked polyubiquitin on signaling hubs and chromatin regulators, catalyzing isopeptide hydrolysis via its papain-like catalytic cysteine. This deubiquitination stabilizes or remodels complexes that control MAPK and small GTPase pathways, cell-cycle transitions, apoptosis, and innate immune signaling. I hypothesize that it forms transient assemblies with cytosolic RNA sensors and their adaptors to potentiate antiviral responses; with chromatin modifiers to tune gene expression and apoptosis; and with ER-proximal scaffolds to coordinate trafficking and membrane targeting. These assemblies are stabilized by multivalent protein binding and guided by the USP catalytic architecture that dictates chain-type specificity and subcellular routing.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-A6NCW7.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/A6NCW7"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/A6NCW7/entry","atlas":"/p/A6NCW7"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}