Sehbanul Islam

The ubiquitin-proteasome system (UPS) is a central mechanism for maintaining cellular homeostasis through the regulated turnover of proteins (1,2). Ubiquitination occurs through a cascade of three enzymes: an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase. In this process, ubiquitin is first activated by the E1 enzyme in an ATP-dependent manner and subsequently transferred to an E2 conjugating enzyme. E3 ubiquitin ligases then confer substrate specificity by catalyzing the transfer of ubiquitin from the E2-ubiquitin conjugate to lysine residues on target proteins (3). During ubiquitination, ubiquitin molecules are sequentially linked through one of ubiquitin's seven lysine residues to form polyubiquitin chains. Notably, lysine-11-and lysine-48-linked chains act as canonical signals for recognition and degradation by the 26S proteasome (4).E3 ubiquitin ligases are broadly classified into four major families based on their structural domains and mechanisms of action: RING (Really Interesting New Gene), HECT (Homology to E6AP C-Terminus), U-box, and RBR (RING-between-RING) (3). RING E3 ligases mediate the direct transfer of ubiquitin from the E2 enzyme to the substrate. In contrast, HECT ligases form a transient thioester intermediate with ubiquitin before transferring it to the target protein. Among these families, RING E3 ligases are the largest and most diverse, existing as monomeric, dimeric, or multi-subunit complexes, many of which are assembled around Cullin scaffold proteins (5).By regulating protein stability, E3 ligases control a wide range of essential cellular processes, including cell cycle progression, proliferation, differentiation, autophagy, DNA damage responses, apoptosis, and signal transduction (6)(7)(8)(9)(10). Notably, they modulate key oncogenic signaling pathways, including the PI3K/AKT, β-catenin, and NF-κB pathways, which are critical for cancer cell growth and survival (10,11). Consistent with these roles, dysregulation of E3 ligase expression or activity is a hallmark of many cancers and directly contributes to tumorigenesis (12)(13)(14).The clinical success of proteasome inhibitors, such as bortezomib, provided the first validation of the UPS as a therapeutic target (15). Beyond conventional small-molecule inhibition, the UPS can be hijacked to achieve the selective elimination of oncogenic proteins through targeted protein degradation (TPD) strategies, including proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (16,17). These approaches have transformed the cancer therapeutic landscape by allowing the targeting of previously "undruggable" proteins, such as transcription factors and scaffold proteins (18)(19)(20)(21) This editorial highlights two original research articles and two review articles that collectively illustrate recent advances and emerging challenges in UPS-and TPD-based cancer therapeutics. In a research article, Cen J. et al. (2025) demonstrated that elongation of very-longchain fatty acid protein 2 (ELOVL2)-mediated stabilization of the androgen receptor (AR) contributes to enzalutamide resistance in prostate cancer. Enzalutamide, a second-generation AR inhibitor, is a cornerstone therapy for castration-resistant prostate cancer (CRPC); however, the emergence of drug resistance remains a major clinical challenge. Through bioinformatic analyses and subsequent experimental validation, the authors identified significant upregulation of ELOVL2 in enzalutamide-resistant prostate cancer cells. Furthermore, functional analysis studies revealed that depletion of ELOVL2 markedly suppressed tumor cell proliferation and restored sensitivity to enzalutamide in resistant models. Mechanistically, ELOVL2 promotes enzalutamide resistance by stabilizing AR through inhibition of ubiquitin-proteasome-mediated degradation. However, the mechanism by which ELOVL2 interfaces with the UPS remains to be elucidated.Collectively, these findings identify ELOVL2 as a critical regulator of AR stability, suggesting that targeting ELOVL2 represents a promising therapeutic strategy to overcome enzalutamide 2025) focuses on the E3 ubiquitin ligase TRIM21, a member of the TRIM family with RING-domain E3 ligase activity, and its complex roles in cancer biology. The authors describe the multidomain structure of TRIM21 and its regulation at both transcriptional and post-translational levels. TRIM21's activity has been implicated in diverse biological functions, including tumor proliferation, metabolic reprogramming, resistance to cell death, metastasis, immune escape, and cellular autophagy, by targeting specific substrates for ubiquitination. Importantly, TRIM21 exhibits context-dependent effects in cancer, acting either as a tumor suppressor or oncogene, depending on the target. Finally, they discuss the potential of TRIM21 as a therapeutic target and suggest that better understanding its context-specific functions could inform novel cancer therapies.Despite substantial advances in E3 ligase-based therapeutic strategies, significant gaps remain in the field. Although more than 600 human E3 ligases have been identified, the majority of current PROTACs rely on a limited subset, most notably CRBN and VHL (22,23). Similarly, molecular glues that induce neo-substrate recruitment are known to engage the E3 ligases CRBN and DCAF15 (16). Recent efforts have therefore focused on expanding the E3 ligase repertoire for targeted protein degradation, with alternative ligases, including FBXO22, DCAF1, DCAF15, DCAF16, TRIM21, MDM2, KEAP1, and RNF126, being leveraged to induce the selective degradation of cancer-associated proteins (24,25). TRIM21 has emerged as a versatile E3 ligase for targeted protein degradation, particularly through clustering-dependent activation mechanisms that can selectively degrade multimeric or aggregated proteins. Notably, TRIM21-based molecular glue degraders, such as acepromazine,...

Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules bridging a protein with an E3 ubiquitin ligase, promoting its ubiquitylation and degradation. However, PROTACs are not without limitations, including suboptimal target degradation and the “hook effect,” a phenomenon where high PROTAC concentrations reduce efficacy due to inactive binary complex formation. In this study, we introduce a novel dual-PROTAC strategy utilizing two distinct E3 ligases, such as KEAP1 and VHL, to synergistically degrade KRAS(G12D) and androgen receptor (AR) by promoting ubiquitin chain elongation and also mitigating the hook effect. In conclusion, a dual-E3 ligase approach represents a promising avenue for optimizing PROTAC-based therapeutics.

The Lin-11, Isl-1 and Mec-3 (LIM) domain, discovered in the late 1980s, is an evolutionarily conserved, cysteine-and histidine-rich, Zinc finger domain that mediates protein-protein interactions. LIM domain-containing proteins constitute a large family of nuclear and cytosolic proteins (70 members in humans) that are divided into 4 groups based on domain composition and arrangement, and the subcellular localization [1]. The LIM proteins display diverse cellular functions, including cytoskeleton organization, gene regulation, and cell fate determination.Since LIM proteins have one or more Zn-finger motifs like RING, they are proposed to have E3 ligase activity [2,3]. Indeed, Tanaka et al. identified STAT-interacting LIM protein (SLIM), also called PDLIM2/Mystique, as the first nuclear LIM domain-containing E3 ligase that targets STAT proteins and p65 for ubiquitination-mediated proteasomal degradation and thereby inactivates the STAT and NF-κB signaling [4][5][6]. These findings suggest that LIM proteins might constitute a new family of E3 ubiquitin ligases; however, only a handful have been verified to have E3 ligase activity. Furthermore, the investigation into the role of LIM proteins as E3 ligases within the realm of cancer remains underexplored.Actin-binding LIM protein 1 (ABLIM1), a member of the ABLIM family of group-3 LIM proteins, consists of 4 LIM domains at the N-terminal, and a coiled-coil and HP domain at the C-terminal region. ABLIM1 is initially characterized as a cytoskeleton protein interacting with the actin filaments and regulating actin networks. A few studies reveal low levels and a tumor suppressor role of ABLIM1 in melanoma, nasopharyngeal carcinoma, and glioblastoma; however, the underlying mechanisms governing ABLIM-mediated tumorigenesis remain elusive.In a recent study published in Cell Death and Differentiation, He et al. unravelled an unknown role of ABLIM1 in CRC, shedding light on its distinctive functions and elucidating the intricate molecular mechanisms at play [7]. The authors showed that elevated ABLIM1 expression in CRC patients correlated with shorter disease-free survival, suggesting its potential as a prognostic biomarker for predicting disease relapse in CRC patients. Furthermore, using in vitro and in vivo studies, the authors showed that ABLIM1 functions as an oncogene to promote the growth and liver metastasis of CRC cells, unlike its previously reported tumor suppressive role in other cancer models. An interesting and novel finding of this study is that ABLIM1 functions as an E3 ubiquitin ligase, which catalyses the ubiquitination and degradation of IĸBα. Since IĸBα is a well-known inhibitor of the NF-ĸB signaling pathway, ABLM1-mediated degradation of IĸBα leads to the translocation of NF-ĸB complex (p65/p50) to the nucleus, transcriptional activation of oncogene CCL20. Overall, the study reveals that ABLIM1 functions as an E3 ligase to promote growth and liver metastasis in CRC by activating the oncogenic NF-ĸB-CCL20 axis. This finding underscores the potential of targeting ABLIM1-NF-ĸB-CCL20 oncogenic axis to prevent CRC progression and metastasis.This study holds significant importance from both a basic and clinical perspective. This study discovers another LIM protein, ABLIM1, functioning as an E3 ligase and strengthens the existing hypothesis that the LIM protein family might constitute yet another E3 ligase family. An intriguing revelation emerges as the research unveils that the C-terminal region exhibits autoubiquitination in vitro, suggesting that the E3 ligase activity is associated with the HP domain. However, deletion of LIM domains significantly hinders ABLIM1-mediated IĸBα polyubiquitination, indicating that the LIM domain is essential for ABLIM1 catalytic activity.Other studies show similar observations that deletion of LIM domains of LIM proteins like PDLIM7 and Hic-5 significantly decreased their E3 ligase activity [8,9]. Further investigation is crucial to unravel the molecular mechanisms of ABLIM1 catalytic activity, where the Cterminal region houses the E3 ligase activity, while the N-terminal LIM domains play an essential role in maintaining catalytic function. Understanding how these regions cooperate and influence each other at the molecular level will provide valuable insights into the regulation of E3 ligases. In particular, the role of the ABLIM1 C-terminal coiled-coil domain warrants detailed exploration. In TRIM family E3 ligases, coiled-coil domains promote oligomerization that stabilizes the active E3 conformation and properly positions the E2~ubiquitin conjugate for efficient ubiquitin transfer to substrates. It is plausible that ABLIM1's coiled-coil domain performs a similar function, being critical for its E3 ligase activity and substrate ubiquitination [10]. Furthermore, the LIM domains might facilitate a favourable three-dimensional conformation of ABLIM1, facilitating its E3 ligase activity. High-resolution structural studies can shed light on the conformational changes in ABLIM1 induced by the presence or absence of LIM domains. Determining the 3D structures of both the full-length ABLIM1 and its truncated forms can provide visual clues on how these domains contribute to the protein's overall architecture and function. Studies have also shown that PDLIM2 E3 ligase, along with PDLIM7 LIM E3 ligase or MKRN2 RING E3 ligase, synergistically promotes polyubiquitination and proteasomal degradation of p65 [8,11]. This suggests that the LIM domain might interact with other proteins, enhancing the overall E3 ligase activity of LIM proteins. Therefore, unravelling the specific interactomes of LIM proteins by proteomic analysis will be instrumental in delineating their E3 ligase activity. Notably, the LIM domain of PDLIM2 can catalyse polyubiquitination of STAT3 in vitro, suggesting that the LIM domain might have catalytic activity [6]. Therefore,...

The COVID-19 pandemic, caused by the newly emerged coronavirus SARS-CoV-2, has resulted in unprecedented global health challenges, including millions of infections and deaths. While the direct effects of the virus are critical, the interplay between SARS-CoV-2 and cellular host factors significantly impacts the replication cycle of the virus and the clinical severity of COVID-19. This review provides a comprehensive analysis of host-pathogen interactions, focusing on the functional roles and regulatory mechanisms of SARS-CoV-2 viral proteins. We systematically review the literature to detail how SARS-CoV-2 engages with host cellular machinery, with a specific emphasis on their modulation by E3 ubiquitin ligases. By dissecting these intricate interactions and the impact of E3 ligases on SARS-CoV-2 infection, we aim to uncover novel therapeutic opportunities and strategies to effectively combat COVID-19.

Oncogene Moesin plays critical role in initiation, progression, and metastasis of multiple cancers. It exerts oncogenic activity due to its high-level expression as well as posttranslational modification in cancer. However, factors responsible for its high-level expression remain elusive. In this study, we identified positive as well as negative regulators of Moesin. Our study reveals that Moesin is a cellular target of F-box protein FBXW2. We showed that FBXW2 suppresses breast cancer progression through directing proteasomal degradation of Moesin. In contrast, AKT kinase plays an important role in oncogenic function of Moesin by protecting it from FBXW2-mediated proteasomal degradation. Mechanistically, AKT phosphorylates Moesin at Thr-558 and thereby prevents its degradation by FBXW2 via weakening the association between FBXW2 and Moesin. Further, accumulated Moesin prevents FBXW2-mediated degradation of oncogene SKP2, showing that Moesin functions as an upstream regulator of oncogene SKP2. In turn, SKP2 stabilizes Moesin by directing its non-degradable form of polyubiquitination and therefore AKT-Moesin-SKP2 oncogenic axis plays crucial role in breast cancer progression. Collectively, our study reveals that FBXW2 functions as a tumor suppressor in breast cancer by restricting AKT-Moesin-SKP2 axis. Thus, AKT-Moesin-SKP2 axis may be explored for the development of therapeutics for cancer treatment.