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Open research questions in Ubiquitin and proteasome pathways

49 unresolved questions extracted from the limitations and future-work sections of 177 Ubiquitin and proteasome pathways papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • The molecular basis of USP28 substrate selectivity and func- tional duality is governed by a multi-layered regulatory network rather than the catalytic domain alone. First, tissue-specific cofactors and scaffolding proteins shape substrate availability. In hepatocellular carcinoma, downregulation of miR-216b enables preferential recruitment of KRT1 to sustain IFITM3 expression (42); in triple-negative breast cancer, USP28 stabilizes RecQ family helicases to support cell-cycle progression (59). The cellular context therefore determines which substrate is stabilized. Second, oligomeric state transitions modulate substrate acces- sibility. Under basal conditions, USP28 forms a dimer that restricts recruitment of the PAF1c complex. Genotoxic stress disrupts the USP28-53BP1 interaction, promoting dimer dissociation and ex- posing interfaces for MYC stabilization and PAF1c recruit- ment (17). Third, competitive E3 ligases influence USP28 activity. USP28 and FBXW7 exert antagonistic effects on shared substrates includ- ing c-MYC and NICD. In CLL with del(11q), heterozygous loss of USP28 paradoxically reduces NOTCH1 signaling, suggesting that the context of USP28 loss (hematologic vs. solid tumor) and the availability of alternative E3 ligases determine functional out- comes (60). Fourth, microenvironmental signals redirect USP28 function. Hypoxia activates USP28 through SENP1-mediated deSUMOylation, leading to HIF-1a accumulation (20). ALKBH1-mediated m6A de- methylation increases USP28 mRNA stability, establishing an ALKBH1-USP28-MYC axis that drives M2 macrophage polarization and suppresses CD8+ T-cell and natural killer cell infiltration, gener- ating an immunosuppressive microenvironment (103). DNA damage alters the 53BP1-USP28 binding equilibrium, redirecting the enzyme from p53 stabilization toward MYC maintenance (17). Fifth, genetic background determines functional outcomes. In BRAF-mutant melanoma, USP28 loss stabilizes BRAF and drives resistance to BRAF inhibitors (58); p53 mutation status dictates whether the USP28-53BP1 axis engages in DNA damage responses. Finally, the immune context modifies USP28 relevance. Pan- cancer analyses associate USP28 expression with neutrophil and natural killer cell abundance. In melanoma, USP28 levels predict response to anti-CTLA-4 therapy (104); in hepatocellular carci- noma models, USP28 inhibition combined with anti-PD-1 therapy increases CD8+ T-cell infiltration (105). Collectively, USP28 functional output is the integrated result of tissue-specific substrate availability, E3 competition, oligomeric state, microenvironmental signals, genetic background, and immune context—rather than a binary oncogene or tumor sup- pressor classification. These determinants operate concurrently to set the functional threshold of USP28 in a given tumor.

    Targeting the deubiquitinase USP28 in cancer: navigating context-dependent mechanisms and therapeutic resistance · 2026 · DOI

  • Abstract Introduction TLR7 signaling is indispensable for the development of spontaneous germinal center (GC) and plasma cell (PC); however, the mechanism that restrains GC and PC formation remain incompletely defined.

    E3 Ubiquitin Ligase Peli1 Regulates TLR7-Driven Spontaneous Germinal Center and Plasma Cell Development 2309783 · 2026 · DOI

  • Abstract Most ubiquitin specific protease (USP) deubiquitinases (DUBs) combine non-selective catalytic domains with one or multiple ‘exo’-domains that contribute substrate specificity and localisation, but are generally poorly characterised.

    ZnF-UBP domains regulate deubiquitinase activity by relieving ubiquitin product inhibition · 2026 · DOI

  • Somatic mutations rewire the ubiquitin-proteasome system (UPS) to support tumor growth, but the proteome-wide consequences of cancer-driver alterations on UPS composition remain incompletely understood.

    Pan-cancer proteogenomic interrogation of the ubiquitin-proteasome system · 2026 · DOI

  • These findings shed light on the function of two poorly understood proteins in regulating PP4 activity, p53 signaling, mitosis and cancer cell survival.

    The regulation of protein phosphatase 4 by FBXO42 is required for cancer cell survival · 2026 · DOI

  • High-throughput approaches indicate that FBXO42 function correlates with that of CCDC6, and that the two proteins interact physically, but the relationship between these proteins is not understood.

    The regulation of protein phosphatase 4 by FBXO42 is required for cancer cell survival · 2026 · DOI

  • Although they appear to target principally immune cell components, such as MHC class II molecules and the co-stimulatory molecule CD86, the repertory of their targets remains to be fully documented.

    A Proximity ligation screen identifies snat2 as a novel target of the MARCH1 E3 ubiquitin ligase · 2026 · DOI

  • The DEAD-box ATPase Dhh1 (DDX6 in humans) is a general activator of 5-3 mRNA decay that acts between the deadenylation and decapping steps of the pathway, although the exact mechanism of its action remains unclear.

    Deadenylation and Decapping Factors Cooperatively Stimulate Biochemical Activities of DEAD-Box ATPase Dhh1 · 2026 · DOI

  • While the intracellular proteostasis network (PN) is well‐characterised, proteostasis mechanisms acting in the extracellular space remain understudied.

    Combating ageing beyond the cell: Emerging roles of extracellular proteostasis · 2026 · DOI

  • Coordination between innate immune signaling and glucose metabolism is fundamental to organismal homeostasis, yet despite decades of study linking immunity and metabolism, the mechanisms by which metabolic cells restrain antiviral innate signaling while preserving glycolytic competence during overnutrition remain poorly defined.

    Tetherin enforces an immunometabolic checkpoint that coordinates glycolytic and interferon signaling in adipocytes · 2026 · DOI

  • The precise mechanism by which TRIM5α restricts HSV-1 through its interaction with VP19C, whether affecting VP19C intracellular trafficking or its function during capsid protein nuclear entry, assembly and egress, or activation of innate immunity, remains to be determined.

    Independent proviral and antiviral host factors recognize the same capsid protein in divergent human herpesviruses · 2026 · DOI

  • Further study of PML function and the targeting of PML nuclear bodies in HBV-infected hepatocytes could reveal new ways to enhance the effectiveness of CAMs.

    PML nuclear bodies orchestrate the storage and degradation of aggregated HBc in the nucleus and reduce CAM-A-induced apoptosis. · 2026 · DOI

  • Given the central role of FANCI in DNA repair, potential on- target toxicities must be carefully evaluated before utilizing in clinical case. Animal experiments demonstrate that FANCI’ s knockdown link to reproduction disorders, including embryonic lethality, male infertility and female POI (25, 94). To address reproductive toxicity, the PCN-222-Mn nanozyme crosses the blood-testis barrier, scavenges ROS, and enhances autophagy (95), while co-delivery micelles package chemotherapeutics with ovarian protectants (96). Combination regimens also hold promise. The optimal ratio of palbociclib (5 µM) to talazoparib (500 nM) achieves strong synergy (CI < 1), potentially minimizing toxicity via lower individual doses (63). Notably, preclinical studies have demon- strated that SKY-1214, which degrades FANCI and FANCL TABLE 2 The role of FANCI in disease diagnosis, treatment and prognosis assessment.

    FANCI: from genome guardian to translational therapeutic target · 2026 · DOI

  • ElaD, a CE clan DUB expressed by enterohemorrhagic Escherichia coli, preferentially cleaves K63 linked ubiquitin chains, yet its effects on conserved cellular stress responses remain poorly understood.

    Redox-modulated bacterial deubiquitinase ElaD: Target recognition and suppression of K63-linked polyubiquitin accumulation in yeast. · 2026 · DOI

  • As a poorly characterized member of the plant-specific D-subgroup MAPKs, MAPK16 harbors a distinctive C-terminal domain that endows it with multiple critical functions, serving as a core positive regulator of maize resistance against F.

    A new plant SUMO ligase, MPEL1, synergizes with MAPK16 to regulate resistance against Fusarium pathogens · 2026 · DOI

  • 1 Co-translational ubiquitination (CTU) is a critical surveillance mechanism,2,3 yet its regulatory principles remain unclear due to limited known substrates and the lack of translatome-wide methods to query CTU.

    Ubiquitin selective ribosome profiling reveals systematic principles of co-translational quality control · 2026 · DOI

  • Although its interactions with cofactors are wellcharacterized, and its dysregulation is implicated in multisystem proteinopathy, amyotrophic lateral sclerosis, and cancer, the tissue-specific VCP interactomes underlying its functional versatility remain elusive.

    Quantitative Proteomics Unveils Comprehensive Tissue-Specific VCP Interaction Networks in Mice · 2026 · DOI

  • Together, these findings indicate that cells preserve proteasome-mediated proteostasis during acute glucose starvation, while NVJ membrane contact sites help sustain degradation capacity when metabolic resources are scarce.

    Proteasome-dependent degradation and nucleus-vacuole junctions sustain proteostasis during acute glucose starvation · 2026 · DOI

  • ARISC-RAP80 contains multiple ubiquitin-binding sites, yet how these influence recognition and cleavage of K63-polyubiquitylated substrates remains unknown.

    Mechanism of K63-linked polyubiquitin recognition and cleavage by the BRCA1-A complex · 2026 · DOI

  • Ubiquitination functions in the occurrence, development, and drug resistance of HCC. Based on the regulation of Wnt/β-catenin, NF-κB, PI3K/AKT/mTOR, and Hippo/YAP signaling pathways, ubiquitination influences cell proliferation, apoptosis, metabolism, and immune escape. For example, abnormal expression of E3 ubiquitin ligases and DUBs has a close relation to the prognosis of HCC, and their dysregulation can alter the stability of key intracellular proteins, thereby affecting tumor progression. Furthermore, ubiquitination is also involved in regulating immune cell function in the tumor microenvironment, impacting HCC immune escape. Despite significant progress in targeted therapy and immunotherapy for HCC, numerous challenges remain. For instance, although targeted drugs such as sorafenib and lenvatinib have extended patient survival, their objective response rate (ORR) as well as progression-free survival (PFS) still need improvement. In immunotherapy, although combinations of immune checkpoint inhibitors and anti-angiogenic drugs have become the first-line treatment standard for advanced HCC, some patients still develop resistance. In the future, ubiquitination system-targeted therapeutic strategies are expected to emerge as new breakthrough directions. For example, by inhibiting the activity of E3 ligases or DUBs, protein homeostasis within tumor cells can be modulated, thereby affecting tumor proliferation and drug resistance. Additionally, developing individualized treatment regimens based on patient molecular subtypes through multi-omics technology is also an important direction for future HCC treatment[177]. Multi-omics integration and translational medical research are crucial for deepening our understanding of the molecular mechanisms of HCC and developing new treatment strategies. By the integration of multi-omics data, phosphorylationomics, and ubiquitinationomics, the molecular regulatory ARTICLE IN PRESSACCEPTED MANUSCRIPTARTICLE IN PRESS networks in HCC can be comprehensively revealed. For example, the application of ultra-high-resolution mass spectrometry aids in discovering new ubiquitination modification sites and regulatory pathways. Furthermore, CRISPR screening technology can systematically identify key ubiquitination regulatory genes in HCC. The combination of these technologies not only aids in discovering new therapeutic targets but also provides more precise guidance for clinical treatment. Translational medical research emphasizes rapidly transferring basic research results into clinical applications, validating the efficacy and safety of new treatment strategies through clinical trials. Therefore, multi-omics integration and translational medical research are important means for promoting precision treatment of HCC, potentially offering patients more treatment options and better prognoses.

    The role of e3 ubiquitin ligases and deubiquitinating enzymes in hepatocellular carcinoma · 2026 · DOI

  • Side effects and off-target toxicities of drugs targeting RNF20 require more in-depth exploration and adequate validation. Systematic characterization of adverse effects in normal tissues and organ systems is needed to establish the clinical safety profile of RNF20-targeting therapeutics.

    Decoding RNF20: an epigenetic modifier and beyond · 2026 · DOI

  • The full spectrum of RNF20/RNF40-H2Bub1 machinery activities across different cellular environments and context-dependent gene expression regulation remains poorly understood. Comprehensive mapping of RNF20 transcriptional targets and epigenetic outcomes in diverse cellular contexts is warranted.

    Decoding RNF20: an epigenetic modifier and beyond · 2026 · DOI

  • LBH589 monotherapy and albendazole-RNF20 inhibition show efficacy in animal models and cell lines, but no large-scale human clinical trials have yet confirmed safety and efficacy profiles for cancer therapy. Phase I/II clinical trials are needed to translate these laboratory findings into standard cancer treatment protocols.

    Decoding RNF20: an epigenetic modifier and beyond · 2026 · DOI

  • The mechanism underlying antagonistic effects when LBH589 is combined with MTX or 6MP in ALL treatment has only been theoretically proposed. Direct experimental validation of whether LBH589 as a pan-HDAC inhibitor interferes with MTX and 6MP intracellular metabolism is needed to clarify these drug-drug interactions.

    Decoding RNF20: an epigenetic modifier and beyond · 2026 · DOI

  • The exact roles of RNF20 in different types or subtypes of cancers and at different tumor stages remain incompletely characterized. Determining cancer-type and stage-specific RNF20 functions is necessary before RNF20 can be exploited as a therapeutic target in distinct malignancies.

    Decoding RNF20: an epigenetic modifier and beyond · 2026 · DOI

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49 open questions have been extracted from the limitations and future-work passages of 177 Ubiquitin and proteasome pathways papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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