Disorders of ubiquitylation: unchained inflammation

Abstract

Ubiquitylation is an essential post-translational modification that regulates intracellular signalling networks by triggering proteasomal substrate degradation, changing the activity of substrates or mediating changes in proteins that interact with substrates. Hundreds of enzymes participate in reversible ubiquitylation of proteins, some acting globally and others targeting specific proteins. Ubiquitylation is essential for innate immune responses, as it facilitates rapid regulation of inflammatory pathways, thereby ensuring sufficient but not excessive responses. A growing number of inborn errors of immunity are attributed to dysregulated ubiquitylation. These genetic disorders exhibit broad clinical manifestations, ranging from susceptibility to infection to autoinflammatory and/or autoimmune features, lymphoproliferation and propensity to malignancy. Many autoinflammatory disorders result from disruption of components of the ubiquitylation machinery and lead to overactivation of innate immune cells. An understanding of the disorders of ubiquitylation in autoinflammatory diseases could enable the development of novel management strategies.

VEXAS Syndrome: A Novelty in MDS Landscape

“…Like diseases with alterations of the ubiquitylation and proteasome system [ 7 ], the clinico-biological presentation of this VEXAS syndrome is very heterogeneous. Typically, VEXAS patients present a systemic inflammatory disease with unexplained episodes of fever, involvement of the lungs, skin, blood vessels and joints.…”

“…In a detailed review of diseases involving deregulation of the ubiquitin–proteasome system, Beck suggests that the development of substrate-specific activator molecules, such as UBA1 in VEXAS syndrome or targeting the proteasome, could be beneficial in the management of these complex diseases. They also propose that one solution may be to inhibit cellular stress pathways such as the UPR pathway that are frequently activated in IAD [ 7 ]. The disappearance of the UBA1 clone at molecular sequencing after the introduction of a new therapeutic line would indeed be a good argument for the effectiveness of the treatment [ 18 ].…”

Vasculitis associated with VEXAS syndrome: A literature review

“…In this process, ubiquitin covalently binds to the substrate sequentially. Ubiquitylation is essential for multiple cellular processes such as cell cycle progression, DNA damage response, and immune signaling pathways ( 20 , 21 ). Thus, dysregulation of the ubiquitin-proteasome system results in many disease states, such as infantile neurodegeneration, susceptibility to infection, lymphoproliferative disorders, and malignancy ( 21 – 23 ).…”

“…Ubiquitylation is essential for multiple cellular processes such as cell cycle progression, DNA damage response, and immune signaling pathways ( 20 , 21 ). Thus, dysregulation of the ubiquitin-proteasome system results in many disease states, such as infantile neurodegeneration, susceptibility to infection, lymphoproliferative disorders, and malignancy ( 21 – 23 ). Several autoinflammatory diseases have also been linked to alterations in the ubiquitylation system ( 24 ).…”

“…More than half of myeloid and erythroid precursor cells harbor such loss-of-function mutations ( 11 ). Therefore, somatic mutations found in VEXAS syndrome lead to a reduction in cytoplasmic UBA1 function, and the resultant decreased ubiquitylation activates the unfolded protein response and type I interferon production ( 21 ). Indeed, transcriptome analysis of the peripheral blood from patients with VEXAS syndrome showed highly activated inflammatory signatures in multiple pathways, including TNF, interleukin-6 (IL-6), interferon-γ, and IL-8 ( 11 ).…”