Ubiquitination

Ubiquitination, a critical posttranslational modification (PTM), involves the enzymatic covalent attachment of ubiquitin to target proteins. This process is fundamental for maintaining cellular homeostasis and regulating key biological functions. The ubiquitination pathway, orchestrated by ubiquitin and its associated enzymes, offers remarkable versatility, acting as a cellular sentinel to ensure precise spatiotemporal control of essential molecular processes. Importantly, the components and mechanisms of ubiquitination can be finely tuned in various ways. Dysregulation of this system can disrupt normal biological processes and contribute to the development of various serious human diseases. These findings underscore the importance of investigating ubiquitination to understand disease mechanisms and develop effective treatment strategies. In this review, we summarize the historical developments and key milestones in ubiquitination research, with a focus on its roles in both health and disease. We explore the components and mechanisms involved, the relevant signaling pathways and their crosstalk, and the multilayered regulatory functions of ubiquitination under physiological and pathological conditions. The pathological contexts discussed include cancer, neurodegenerative disorders, cardiovascular diseases, inflammatory conditions, autoinflammatory disorders and developmental disorders. Enhancing our understanding of ubiquitination could provide novel insights into disease pathogenesis and identify new therapeutic targets. We also highlight emerging strategies for cancer treatment, such as proteolysis-targeting chimeras (PROTACs) and molecular glues. Furthermore, we review therapeutic targets and recent progress in clinical research, including ongoing clinical trials and FDA-approved drugs, aimed at leveraging the ubiquitination pathway for disease treatment.

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are overwhelmingly linked to TDP-43 dysfunction. Mutations in TDP-43 are rare, indicating that the progressive accumulation of exogenous factors - such as cellular stressors - converge on TDP-43 to play a key role in disease pathogenesis. Post translational modifications such as SUMOylation play essential roles in response to such exogenous stressors. We therefore set out to understand how SUMOylation may regulate TDP-43 in health and disease. We find that TDP-43 is regulated dynamically via SUMOylation in response to cellular stressors. When this process is blocked in vivo, we note age-dependent TDP-43 pathology and sex-specific behavioral deficits linking TDP-43 SUMOylation with aging and disease. We further find that SUMOylation is correlated with human aging and disease states. Collectively, this work presents TDP-43 SUMOylation as an early physiological response to cellular stress, disruption of which may confer a risk for TDP-43 proteinopathy.

Colorectal cancer (CRC) is one of the most common gastrointestinal tumors, and one of the leading causes of cancer-related deaths worldwide. However, the molecular mechanisms underlying CRC development and progression have not been fully elucidated until now. Emerging studies have shown that post-translational modifications of proteins, especially ubiquitination modifications, play an important role in tumorigenesis and progression. Here we identified that the E3 ligase TRIM31, a member of the TRIM (Tripartite Motif) family proteins, is highly expressed during colorectal inflammation-cancer transformation and is associated with poor prognosis in CRC patients. Knockdown of TRIM31 expression led to the suppression of CRC cell proliferation and migration in vitro, tumor formation and metastatic ability in vivo. TRIM31 interacts with YBX1 and catalyses the Lys63 (K63) linkage polyubiquitination of Lys81 on YBX1, which ultimately leads to the stabilization of the YBX1 protein. YBX1 further enhances the stabilization of mRNAs for EREG, GAS6, and MAFG through both m5C site-dependent and -independent recognition routes. In addition, activation of NF-κB promotes the binding of P65 to the promoter region of TRIM31 to activate the transcription of the TRIM31 gene. Furthermore, TRIM31 facilitates the entry of P65 into the nucleus, which in turn creates a positive feedback pathway that promotes inflammatory-carcinogenic transformation and tumorigenesis of colorectal. Our findings indicate that TRIM31 may be an important factor driving colorectal carcinogenesis, providing a potential target for intervention in CRC targeted therapy.

Postmenopausal osteoporosis (PMOP) has a high incidence in middle-aged and elderly women, leading to an increased risk of fractures and elevated rates of disability and mortality. In this work, we identified the reduction of indole-3-propionic acid (IPA) as a potential key factor contributing to the decline in bone mass observed in postmenopausal women. Mechanistically, IPA activates AhR, leading to the stabilization of key proteins in Wnt and NF-κB pathways that regulate bone formation and resorption. We evaluated efficacy in vivo using eight-week-old female C57BL/6 mice subjected to bilateral ovariectomy (OVX), with treatments initiated one week postsurgery, and performed complementary in vitro assays. Intraperitoneal IPA (20 mg/kg, 3× per week for 8 weeks) increased the trabecular bone mineral density (Tb.BMD) by ~68% versus OVX controls, whereas engineered Clostridium sporogenes that enhances IPA biosynthesis led to an even greater increase of ~118%. Together, these findings highlight the gut-bone axis as a central framework linking microbiota-derived IPA to skeletal remodeling and provide preclinical proof-of-concept for an engineered C. sporogenes-IPA strategy with therapeutic potential in PMOP.