# USP10 notes

Review started from `just fetch-gene human USP10`. The proteostasis network places USP10 in ATG8/LC3 deubiquitination, ribosome-associated quality control, and USP-family deubiquitinase contexts.

Falcon deep research was requested with `just deep-research-falcon human USP10`. The provider returned a 503 retry and timed out after 600 seconds, so no usable `USP10-deep-research-falcon.md` was generated. The review below is based on cached UniProt/GOA/Reactome/publication evidence and the PMID-resolved PN LC3B source.

USP10 is a ubiquitin-specific cysteine deubiquitinase. UniProt names it "Ubiquitin carboxyl-terminal hydrolase 10" and lists EC 3.4.19.12; multiple experimental publications support catalytic deubiquitinase activity. A general Reactome entry states that "Deubiquitinating enzymes (DUBs) catalyze the removal of Ub and regulate Ub-mediated pathways" [Reactome:R-HSA-5688426 "Deubiquitination"], while substrate-specific papers show USP10 removing ubiquitin from p53, CFTR, ribosomal proteins, and LC3B.

The p53 axis is a well-supported but substrate/context-specific USP10 function. Yuan et al. report that "USP10, a cytoplasmic ubiquitin-specific protease, deubiquitinates p53" and that after DNA damage "a fraction of USP10 translocates to the nucleus to activate p53" [PMID:20096447 "USP10 regulates p53 localization and stability by deubiquitinating p53."]. This supports cysteine-type deubiquitinase activity, protein deubiquitination, p53 binding, cytoplasm/nucleus localization, and p53-class DNA damage signaling, but the core molecular function remains DUB activity rather than generic DNA damage response.

USP10 has a direct early-endosome/channel trafficking substrate in CFTR. Bomberger et al. found that "USP10 is located in early endosomes and regulates the deubiquitination of CFTR" and that knockdown increased ubiquitinated CFTR, lysosomal degradation, and decreased chloride secretion [PMID:19398555 "The deubiquitinating enzyme USP10 regulates the post-endocytic sorting of cystic fibrosis transmembrane conductance regulator in airway epithelial cells."]. The same paper states that USP10 facilitates "the deubiquitination of CFTR in early endosomes and thereby enhancing the endocytic recycling of CFTR" [PMID:19398555]. This supports early endosome localization and a specific transporter-binding/substrate context, but not a broad transporter function.

Autophagy regulation is supported through Beclin1 and LC3B substrates. Liu et al. report that spautin-1 inhibits "two ubiquitin-specific peptidases, USP10 and USP13, that target the Beclin1 subunit of Vps34 complexes" and that "Beclin1 also controls the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities" [PMID:21962518 "Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13."]. More directly for the PN ATG8 context, Jia et al. report that "LC3B ubiquitination is reversed by the action of the deubiquitinating enzyme USP10"; USP10 silencing reduces LC3B-I and LC3B-II through increased ubiquitination/proteasomal degradation, and "LC3B and autophagic activity are controlled through cycles of LC3B ubiquitination and deubiquitination" [PMID:33577797 "The ubiquitin isopeptidase USP10 deubiquitinates LC3B to increase LC3B levels and autophagic activity."]. Current GO can capture this only as broad protein deubiquitination or regulation of autophagy; a more specific ATG8-family protein deubiquitination term would be useful.

USP10 has a direct ribosome-associated quality-control function on ubiquitinated 40S subunits. Meyer et al. report that "G3BP1-family-USP10 complexes are required for deubiquitination of RPS2, RPS3, and RPS10 to rescue modified 40S subunits from programmed degradation" [PMID:31981475 "The G3BP1-Family-USP10 Deubiquitinase Complex Rescues Ubiquitinated 40S Subunits of Ribosomes Stalled in Translation from Lysosomal Degradation."]. Garzia et al. similarly state that impeded ribosomes are tagged on the 40S subunit "for subsequent programmed degradation unless rescued by USP10" [PMID:34348161 "The E3 ubiquitin ligase RNF10 modifies 40S ribosomal subunits of ribosomes compromised in translation."]. Garshott et al. identify "the deubiquitylating enzyme USP10 as the key" enzyme for uS3/uS5 ribosomal ubiquitylation and state that loss of USP10 causes enhanced uS3/uS5 ubiquitylation, while USP10 overexpression removes observable ribosomal ubiquitylation in an activity-dependent manner [PMID:34469731 "iRQC, a surveillance pathway for 40S ribosomal quality control during mRNA translation initiation."]. These support cytosolic ribosome, monoubiquitinated protein deubiquitination, and rescue of stalled cytosolic ribosome as direct proteostasis functions.

USP10 is linked to stress-granule regulation through G3BP binding rather than a broad catalytic autophagy mechanism. Kedersha et al. report that "Caprin binding promotes, but USP10 binding inhibits, SG formation" and that G3BP interacts with 40S subunits through its RGG motif [PMID:27022092 "G3BP-Caprin1-USP10 complexes mediate stress granule condensation and associate with 40S subunits."]. Yang et al. model stress granule and P-body organization as RNA/protein networks in which "competitive binding of unconnected proteins disengages networks and prevents LLPS" [PMID:32302570 "Competing Protein-RNA Interaction Networks Control Multiphase Intracellular Organization."]. These support negative regulation of stress granule assembly and molecular function inhibitor activity as non-core, context-specific roles. Generic protein binding should remain over-annotated.

The NF-kappaB/IL-1 annotations are also supported but non-core. Wang et al. show that TANK forms a complex with MCPIP1/ZC3H12A and USP10 and that this was essential for "USP10-dependent deubiquitination of TRAF6 and the resolution of genotoxic NF-kappaB activation upon DNA damage" [PMID:25861989 "TRAF Family Member-associated NF-kappaB Activator (TANK) Inhibits Genotoxic Nuclear Factor kappaB Activation by Facilitating Deubiquitinase USP10-dependent Deubiquitination of TRAF6 Ligase."]. The same abstract reports that the TANK-MCPIP1-USP10 complex decreased TRAF6 ubiquitination in cells treated with IL-1beta or LPS and that USP10 depletion enhanced NF-kappaB activation [PMID:25861989]. This supports non-core negative regulation of canonical NF-kappaB signaling, cellular response to IL-1, protein complex participation, and DNA-damage-linked signaling.

Innate immune annotations should be handled carefully. The GOA-seeded annotation cites the KSHV vIRF1/SIRT6 paper, where vIRF1 blocks "SIRT6's interaction with ubiquitin-specific peptidase 10 (USP10)" leading to SIRT6 degradation [PMID:37023208 "Immune evasion strategy involving propionylation by the KSHV interferon regulatory factor 1 (vIRF1)."]. That is indirect for USP10 as an innate immune effector. However, a separate MAVS paper provides direct USP10 immune evidence: "USP10 as a direct DUB that removes unanchored K63-linked polyubiquitin chains from MAVS" and attenuates RIG-I-mediated MAVS aggregation and type I interferon production [PMID:37582970 "MAVS-loaded unanchored Lys63-linked polyubiquitin chains activate the RIG-I-MAVS signaling cascade."]. I will keep innate immune response as a non-core regulatory context with this caveat rather than making it a core function.

The high-throughput RNA-binding annotations (PMID:22658674 and PMID:22681889) are broad RBP-atlas style evidence. USP10 has G3BP/40S/stress-granule contexts, but the current evidence does not make RNA binding a core USP10 molecular function. Treat RNA binding as non-core or over-annotated depending on validation consistency; do not use it as a core function.

Annotation stance:
- Core molecular function: cysteine-type deubiquitinase activity (GO:0004843), directly involved in protein deubiquitination (GO:0016579).
- Direct proteostasis processes to accept: monoubiquitinated protein deubiquitination (GO:0035520) and rescue of stalled cytosolic ribosome (GO:0072344), supported by 40S/RQC papers.
- Direct cellular locations/activity sites: cytoplasm/cytosol, nucleus/nucleoplasm for p53/Reactome contexts, early endosome for CFTR, and cytosolic ribosome for RQC.
- Non-core but supported contexts: regulation of autophagy (Beclin1/LC3B), p53-class DNA damage response, translesion synthesis/PCNA deubiquitination, stress-granule inhibition, NF-kappaB/IL-1 regulation, MAVS/RLR innate immune regulation, p53 binding, CFTR/transporter binding, RNA binding.
- Modify cysteine-type endopeptidase activity (GO:0004197) to cysteine-type deubiquitinase activity (GO:0004843).
- Mark generic protein binding (GO:0005515) as over-annotated; when meaningful, capture the specific substrate/context in notes and replacement questions rather than keeping a generic MF term.

## Description cleanup note

The YAML `description` field was revised to keep it as a standalone biological summary. Project-specific curation framing moved here instead.

- Moved out of the YAML description: the prior wording framed USP10's most direct roles in the Proteostasis Network as protein deubiquitination, rescue of ubiquitinated stalled 40S ribosomal subunits, and non-core regulation of autophagy/stress-granule signaling through LC3B, Beclin1, and G3BP contexts.