CYLD-Mediated Signaling and Diseases

Abstract

The conserved cylindromatosis (CYLD) codes for a deubiquitinating enzyme and is a crucial regulator of diverse cellular processes such as immune responses, inflammation, death, and proliferation. It directly regulates multiple key signaling cascades, such as the Nuclear Factor kappa B [NF-kB] and the Mitogen-Activated Protein Kinase (MAPK) pathways, by its catalytic activity on polyubiquitinated key intermediates. Several lines of emerging evidence have linked CYLD to the pathogenesis of various maladies, including cancer, poor infection control, lung fibrosis, neural development, and now cardiovascular dysfunction. While CYLD-mediated signaling is cell type and stimuli specific, the activity of CYLD is tightly controlled by phosphorylation and other regulators such as Snail. This review explores a broad selection of current and past literature regarding CYLD’s expression, function and regulation with emerging reports on its role in cardiovascular disease.

SPATA2-Mediated Binding of CYLD to HOIP Enables CYLD Recruitment to Signaling Complexes

“…Because SPATA2 also requires HOIP for its recruitment to the NOD2-SC, we deem it likely that the complex consisting of LUBAC, SPATA2, and CYLD is the default complex recruited also to other receptor-associated complexes known to involve CYLD and/or LUBAC (Douanne et al., 2016, Tauriello et al., 2010). Given the growing relevance of the equilibrium between ubiquitination and deubiquitination in the regulation of signaling complexes (Harhaj and Dixit, 2012, Kupka et al., 2016, Yau and Rape, 2016) and the involvement of CYLD in a wide number of signaling platforms (Draber et al., 2015, Mathis et al., 2015, Reiley et al., 2006, Tauriello et al., 2010, Zhang et al., 2011), the discovery of SPATA2 as a previously unrecognized adaptor between CYLD and HOIP by us and others (Wagner et al., 2016) provides additional insight on the mechanisms by which this DUB controls the outcome of these diverse signaling processes.…”

Down-regulation of the Tumor Suppressor CYLD Enhances the Transformed Phenotype of Human Breast Cancer Cells

“…Down-regulation of CYLD expression has been correlated with the development of various types of human malignancies (2). However, the causative role of CYLD down-regulation in the deregulation of homeostatic mechanisms of various cell types that lead to transformation has not been established.…”

CYLD – a deubiquitylase that acts to fine-tune microtubule properties and functions

“…Since the identification of Cyld as a tumor suppressor gene (Bignell et al, 2000), we have witnessed great advances in our understanding of its functions in pathological and physiological processes, including in tumor initiation and progression, immune system development and responses, spermatogenesis, lung maturation and osteogenesis (Hellerbrand and Massoumi, 2016;Massoumi, 2011;Mathis et al, 2015;Sun, 2010). Despite these important findings, we are only just beginning to understand the underlying mechanisms by which CYLD regulates these diverse processes.…”

“…It is worth noting that whether and how CYLD participates in the regulation of immune cell motility has not yet been reported, although the role of CYLD in immune system development, and immune and inflammatory responses has already been extensively studied (Mathis et al, 2015;Sun, 2010). Loss of CYLD has also been demonstrated to stimulate the formation of inflammationassociated cancers, such as colorectal, skin and liver cancers (Massoumi et al, 2006;Nikolaou et al, 2012;Zhang et al, 2006).…”