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Post-translational modifications play a fundamental role in regulating protein function and stability. In particular, protein ubiquitylation is a multifaceted modification involved in numerous aspects of plant biology. Landmark studies connected the ATP-dependent ubiquitylation of substrates to their degradation by the 26S proteasome; however, nonproteolytic functions of the ubiquitin (Ub) code are also crucial to regulate protein interactions, activity, and localization. Regarding proteolytic functions of Ub, Lys-48-linked branched chains are the most common chain type for proteasomal degradation, whereas promotion of endocytosis and vacuolar degradation is triggered through monoubiquitylation or Lys63-linked chains introduced in integral or peripheral plasma membrane proteins. Hormone signaling relies on regulated protein turnover, and specifically the half-life of ABA signaling components is regulated both through the ubiquitin-26S proteasome system and the endocytic/vacuolar degradation pathway. E3 Ub ligases have been reported that target different ABA signaling core components, i.e., ABA receptors, PP2Cs, SnRK2s, and ABFs/ABI5 transcription factors. In this review, we focused specifically on the ubiquitylation of ABA receptors and PP2C coreceptors, as well as other post-translational modifications of ABA receptors (nitration and phosphorylation) that result in their ubiquitination and degradation.

The mitochondrial antiviral-signaling protein (MAVS), a core adaptor protein in the retinoic-acid-inducible gene-I-like receptors (RLRs)-MAVS pathway, has been demonstrated to play an important role in antiviral immune response and tumor immunology. Previous studies revealed that ubiquitylation is a key mechanism in the regulation of the RLRs-MAVS axis and immune response. Multiple E3 ubiquitin ligases and deubiquitinating enzymes control MAVS ubiquitylation and changes in MAVS function. In this review, we summarize the biological function of ubiquitylation in MAVS-related signaling and provide new insight into immunotherapy approaches that target MAVS.

In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4–RBX1–DDB1–CRBN (known as CRL4 CRBN ) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4 CRBN . Here we present crystal structures of the DDB1–CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4 CRBN and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4 CRBN . Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4 CRBN while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins. The crystal structures of thalidomide and its derivatives bound to the E3 ligase subcomplex DDB1–CRBN are shown; these drugs are found to have dual functions, interfering with the binding of certain cellular substrates to the E3 ligase but promoting the binding of others, thereby modulating the degradation of cellular proteins. Thalidomide's dual mechanism of action Introduced in Europe in 1957 as a mild sedative, thalidomide was widely used in pregnant women as a treatment for morning sickness. This led to the birth of thousands of children with multiple defects and the drug was withdrawn in 1962. Since then thalidomide and its derivatives have emerged as effective treatments for the cancer multiple myeloma and the associated disorder 5q-dysplasia. The primary teratogenic target of thalidomide is cereblon (CRBN), part of E3 ubiquitin ligase complex CUL4–RBX1–DDB1–CRBN (CRL4 CRBN ). Here, Nicolas Thomä and colleagues present the crystal structure of DDB1–CRBN E3 ubiquitin ligase bound to thalidomide and to the related drugs lenalidomide and pomalidomide. The structure establishes the molecular mechanism underlying CRBN's enantioselective action. Further structure–function analysis reveals that these drugs have dual functions, interfering with the binding of certain cellular substrates to the E3 ligase but promoting the binding of others, thereby modulating the degradation of cellular proteins.

• Plant organs often grow into a genetically determined size and shape. How organ growth is finely regulated to achieve a well defined pattern is a fascinating, but largely unresolved, question in plant research. • We utilised the Arabidopsis petal to study the genetic control of plant organ growth, and identify two closely related U-box E3 ligases PUB25 and PUB26 as important growth regulators by screening the targets of the petal-specific growth-promoting transcription factor RABBIT EARS (RBE). • We showed that PUB25 is directly controlled by RBE in petal development in a spatial- and temporal-specific manner and acts as a major target to mediate RBE’s function in petal growth. We also showed that PUB25 and PUB26 repress petal growth by restricting the period of cell proliferation, and their regulation appears to be independent of other plant E3 ligase genes implicated in growth control. • PUB25 and PUB26 are among the first U-box E3 ligases shown to function in plant growth control. Furthermore, as they were also found to play a vital role in plant stress responses, PUB25 and PUB26 may act as a key hub to integrate developmental and environmental signals for balancing growth and defence in plants.

Membrane-associated RING-CH (MARCH) E3 ubiquitin ligases, a family of RING-type E3 ubiquitin ligases, have garnered increased attention for their indispensable roles in immune regulation, inflammation, mitochondrial dynamics, and lipid metabolism. The MARCH E3 ligase family consists of eleven distinct members, and the dysregulation of many of these members has been documented in several human malignancies. Over the past two decades, extensive research has revealed that MARCH E3 ligases play pivotal roles in cancer progression by ubiquitinating key oncogenes and tumor suppressors and orchestrating various signaling pathways. Some MARCH E3s act as oncogenes, while others act as tumor suppressors, and the majority of MARCH E3s play both oncogenic and tumor suppressive roles in a context-dependent manner. Notably, there is special emphasis on the sole mitochondrial MARCH E3 ligase MARCH5, which regulates mitochondrial homeostasis within cancer cells. In this review, we delve into the diverse functions of MARCH E3 ligases across different cancer types, shedding light on the underlying molecular mechanisms mediating their effects, their regulatory effects on cancer and their potential as therapeutic targets.

Thalidomide, lenalidomide and pomalidomide are immunomodulatory drugs (IMiDs) effective in the treatment of multiple myeloma, myelodysplastic syndrome (MDS) with deletion of chromosome 5q and other hematological malignancies. Recent studies showed that IMiDs bind to CRBN, a substrate receptor of CRL4 E3 ligase, to induce the ubiquitination and degradation of IKZF1 and IKZF3 in multiple myeloma cells, contributing to their anti-myeloma activity. Similarly, lenalidomide exerts therapeutic efficacy via inducing ubiquitination and degradation of CK1α in MDS with deletion of chromosome 5q. Recently, novel thalidomide analogs have been designed for better clinical efficacy, including CC-122, CC-220 and CC-885. Moreover, a number of neo-substrates of IMiDs have been discovered. Proteolysis-targeting chimeras (PROTACs) as a class of bi-functional molecules are increasingly used as a strategy to target otherwise intractable cellular protein. PROTACs appear to have broad implications for novel therapeutics. In this review, we summarized new generation of immunomodulatory compounds, their potential neo-substrates, and new strategies for the design of novel PROTAC drugs.

The Suppressor of Cytokine Signalling (SOCS) protein family play a critical role in cytokine signalling and regulation of the JAK/STAT pathway with functional consequences to the immune response. Members of this family are implicated in multiple different signalling cascades that drive autoimmune diseases and cancer, through their binding to phosphotyrosine modified proteins as well as ubiquitination activity as part of Cullin5 RING E3 ligases. Here we review the SOCS family members CISH and SOCS1-SOCS7, with a focus on their complex role in immunity. The interactome and signalling network of this protein family is discussed, and the intricate mechanisms through which SOCS proteins alter and manage the immune system are assessed. We offer structural insights into how SOCS proteins engage their interacting partners and native substrates at the protein-protein interaction level. We describe how this knowledge has enabled drug discovery efforts on SOCS proteins to date and propose strategies for therapeutic intervention using small molecules, either via direct inhibition or leveraging their E3 ligase activity for targeted protein degradation.

CTLH/CRA/RING-containing proteins have been shown to possess E3-ligase activities and are crucial for the regulation of numerous cellular signaling pathways. In our previous studies, SIE3 (SymRK-Interacting E3 ubiquitin ligase), a CTLH/CRA/RING-containing protein from Lotus japonicus, has been shown to associate with both Symbiosis Receptor Kinase (SymRK) and SIP1 (SymRK interacting protein 1) transcription factor, and ubiquitinate SymRK (Yuan et al. Plant Physiol 160 (1):106–117, 2012; Feng et al. Front Plant Sci 11: 795, 2020). Besides, we previously also demonstrated that the residue, cysteine-266 in the CRA (CT11-RanBPM) domain is required for homodimerization of SIE3 and cysteine-266 residue-mediated homodimerization is important for the symbiosic function of SIE3 (Feng et al. 2020). In this report, SIE3 was shown to induce the ubiquitination and degradation of SIP1. The cysteine-266 residue is essential for the E3-ligase activity and is highly conserved in the SIE3-like proteins. Our works refined the working model that homodimerization of SIE3 is required for ubiquitin-related degradation of SIP1 and found a conserved cysteine residue plays a key role in the activity of a plant dimeric E3 ligase.

The ubiquitin–proteasome system is a highly conserved machinery that plays a crucial role in plant defense against viruses. However, the number of E3 ligases targeting viral proteins remains limited. Although RING‐between‐RING (RBR)‐type E3 ligases are evolutionarily conserved across organisms, their functions in plant responses to biotic stress remain largely unknown. Herein, it is found that the triple gene block 1 (TGB1) protein of the barley stripe mosaic virus (BSMV) undergoes ubiquitination during viral infection. Immunoprecipitation combined with mass spectrometry identified an RBR‐type E3 ligase that interacted with TGB1 in vivo and in vitro. The overexpression of Ariadne‐like protein 8 (ARI8) inhibits, whereas its knockout enhances, the local and systemic spread of BSMV. ARI8 mediated the ubiquitination of TGB1, and its Cys311 residue is required for the ARI8‐mediated degradation of TGB1 and inhibition of BSMV infection. In addition to BSMV, ARI8 negatively regulates infection by other TGB‐containing viruses, including potato virus X and beet necrotic yellow vein virus. Collectively, the findings identified a new E3 ligase that targets a plant viral protein and reveals a previously uncharacterized role for RBR‐type E3 ligases in plant responses to biotic stress, providing a potential molecular target for the development of antiviral strategies in plants. The plant RING‐between‐RING (RBR)‐type E3 ligase, Ariadne‐like protein 8 (ARI8), ubiquitinates and degrades a viral movement protein, restricting virus spread. ARI8 also inhibits other triple gene block 1 (TGB1)‐containing viruses, revealing a broad‐spectrum antiviral role. This study uncovers a previously unknown function of RBR‐type E3 ligases in plant immunity and offers a potential target for antiviral crop improvement.

Summary The abscisic acid (ABA) signalling pathway is involved in the plant response to osmotic stress caused by drought and/or salinity. Although the ABA signalling pathway has been elucidated in Arabidopsis, it remains elusive in woody poplars. In this study, genome‐wide analyses of U‐box genes in poplars revealed that a U‐box E3 ubiquitin ligase gene, PalPUB79, is significantly induced following drought, salinity and ABA signalling. PalPUB79 overexpression enhanced drought tolerance in transgenic poplars, while PalPUB79 RNAi lines were more sensitive to drought. PalPUB79 positively regulated ABA signalling pathway. Furthermore, PalPUB79 interacted with PalWRKY77, a negative transcriptional regulator of ABA signalling, and mediated its ubiquitination for degradation, therefore counteracting its inhibitory effect on PalRD26 transcription. However, the finding that PalWRKY77 negatively regulates PalPUB79 expression was indicative of a negative feedback loop between PalWRKY77 and PalPUB79 during ABA signalling in poplar. These findings provide novel insight into the mechanism through which PalPUB79 enhances the ABA‐mediated stress response in woody poplars.