Ubiquitin-mediated post-translational regulation of proteins is an essential mechanism that influences protein structure, function, and stability. Among the E3 ubiquitin ligases, Cbl is of particular interest in the context of signal transduction in T cells and NK cells, where it serves as a key regulator of receptor-linked signaling pathways that control cell activation. In addition to Cbl, other E3 ubiquitin ligases, such as GRAIL, Itch, and members of the TRIM family, play significant roles in immune cell regulation by promoting the ubiquitination and subsequent degradation of critical proteins involved in immune responses.

Cbl promotes the proteasomal degradation of TCR/CD3 subunits in T cells and the degradation of protein kinases Fyn and Lck, which are essential for cell activation. It also regulates the degradation of the scaffold protein LAT in both T cells and NK cells and participates in various regulatory mechanisms at the immunological synapse. Other ubiquitin ligases, such as Itch and GRAIL, contribute to immune tolerance and regulation by targeting distinct substrates, while TRIM family members are involved in antiviral immunity and innate immune signaling.

Recent findings suggest that Cbl mediates the ubiquitination and degradation of C3G via CrkII during early T cell activation, which may also have implications for NK cell signaling. Similarly, E3 ligases such as Itch and GRAIL play roles in maintaining immune homeostasis and preventing autoimmunity by controlling the degradation of key signaling proteins.
This Research Topic covers significant contributions related to Cbl and other ubiquitin ligases in the context of T cell and NK cell function. Selected manuscripts will analyze the roles of the distinct Cbl proteins, as well as GRAIL, Itch, TRIM family members, and other relevant ubiquitin ligases, in the regulation of immune cell responses. Additional manuscripts will review the mechanisms of regulation, including post-translational modifications such as phosphorylation or ubiquitination, or interactions with a wide range of binding partners that lead to conformational changes, proteasomal degradation, or alterations in subcellular localization and enzymatic activity of target proteins.

Additional topics will focus on the biochemical roles of Cbl-b, c-Cbl, GRAIL, Itch, and other E3 ubiquitin ligases in T lymphocyte and NK cell function. These molecules play important and non-redundant roles in T cell activation and immune synapse formation. Manuscripts will describe the role of Cbl and related ligases in promoting the proteasomal degradation of proteins critical for regulating cell activation, including TCR/CD3 subunits, Fyn and Lck protein tyrosine kinases, LAT scaffold protein, and the C3G guanine-nucleotide-exchange factor, as well as proteins targeted by other E3 ligases.

Given their roles in modulating immune responses and their manageable impact on autoimmunity, Cbl and other ubiquitin ligases are being investigated as potential targets for cancer immunotherapy. This collection brings together leading experts from various disciplines to review the latest discoveries and offer new perspectives on the contributions of Cbl isoforms and other ubiquitin ligases to biochemical processes and signaling events in immune cells, and their impact on the host immune response. Specific themes of this Research Topic include, but are not limited to:

• Cbl and related ubiquitin ligases: structure-function relationships
• Ubiquitin-mediated regulation of signal transduction in lymphoid cells
• Regulation of T cell and NK cell responses by Cbl, GRAIL, Itch, and TRIM family ligases
• Ubiquitination and proteasomal degradation in immune cells
• Mechanisms of cell transformation by Cbl and other oncogenic ubiquitin ligases
• Ubiquitin ligases as targets in cancer immunotherapy
• Involvement of ubiquitin ligases in autoimmunity

We are currently accepting Original research, Systematic review, Methods, Review, Mini review, Perspective, Clinical trials, Case report, Brief research report, and Opinion.

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The Role of Ubiquitin Ligases in Regulating Immune Cell Functions: Cbl and Beyond