Biology subjects

Rizk, J.

Publications and source records attributed to Rizk, J..

5 recordsLinked to original sources

bioRxiv2026

Interdependent androgen and glucocorticoid receptor signalling shapes prostate epithelial homeostasis

Androgen signalling is essential for prostate secretory functions and epithelial cell maintenance, yet how this signal is translated into a transcriptional output remains poorly understood. Androgens functions are primarily mediated by the androgen receptor (AR), which binds hormone response elements similar to those of other steroid receptors, including the glucocorticoid receptor (GR). Here we show that AR and GR are co-expressed in the prostate epithelium, and co-located within nuclear foci. Moreover, GR promotes the formation and dynamics of AR nuclear condensates, and heterodimerizes with AR in a ligand-binding domain-dependent manner. In addition, subtle variations within the hormone response element sequence direct the co-recruitment of AR and GR into activator or repressor complexes to activate or repress gene expression. Finally, prostate-specific deletion of GR in mice disrupts AR nuclear distribution, impairs AR-dependent gene networks involved in epithelial maintenance, and promotes the expression of genes involved in metabolism and cell cycle, resulting in altered tissue homeostasis. Thus, these findings identify GR as an integral component of the AR transcriptional machinery in epithelial cells of the healthy prostate, and reveal how shared cis-regulatory elements are interpreted to generate distinct transcriptional outcomes.

cell biology↗

bioRxiv2026

The binding of OTULIN restrains LUBAC activity to prevent TNF-driven immunopathology

Met1-linked ubiquitin chains (Met1-Ub), synthesised by the linear ubiquitin chain assembly complex (LUBAC) and disassembled by the deubiquitinase OTULIN, critically regulate inflammatory signalling. Although OTULINs activity is essential to prevent TNF-driven autoinflammatory pathology and embryonic lethality, the regulatory significance of its direct interaction with LUBAC remains unclear. Here, we reveal that mice harbouring a point mutation (OTULINY56A) in the OTULIN PUB-interacting motif, which disrupts OTULIN-LUBAC interaction, are viable without spontaneous immunopathology. However, OtulinY56A/Y56A mice exhibited hypersensitivity to TNF-induced toxicity, which was not prevented by inhibiting RIPK1 kinase-mediated cell death. Mechanistically, disruption of the OTULIN-LUBAC interaction led to Met1-linked autoubiquitination, which enhanced LUBACs activity and increased Met1-Ub accumulation at the TNF receptor signalling complex. This stabilised the signalling complex even after dissociation from TNF, increased NF-{kappa}B signalling and, contrary to loss of OTULIN or its activity, protected cells from TNF-induced apoptosis. During systemic Listeria monocytogenes infection, the increased response to TNF in OtulinY56A/Y56A mice exaggerated pathology without affecting bacterial burden. Collectively, we identify the physical association of OTULIN to LUBAC as a critical brake that restricts LUBACs function and Met1-Ub-dependent inflammatory signalling, thereby preserving tissue integrity and promoting disease tolerance during acute immune activation.

molecular biology↗

bioRxiv2024

M1-linked Ubiquitination by LUBAC Regulates AMPK Activity and the Response to Energetic Stress

Methionine-1 (M1)-linked ubiquitin chains, assembled by the ubiquitin ligase LUBAC and cleaved by the deubiquitinase OTULIN, are critical regulators of inflammation and immune homeostasis. Genetic loss of either LUBAC or OTULIN causes autoinflammatory syndromes, which are associated with defects in glycogen and lipid metabolism. However, how LUBAC and OTULIN regulate metabolic signalling remains unknown. Here, we demonstrate that LUBAC promotes, while OTULIN restricts, activation of the key metabolic regulator AMP-activated protein kinase (AMPK) in cells, mice, and human samples. LUBAC and OTULIN interact with AMPK, control its M1-ubiquitination, and regulate its activation in response to glucose starvation and allosteric activation. During starvation, LUBAC deficiency impairs autophagy induction and hinders the shift from oxidative phosphorylation to glycolysis. Strikingly, LUBAC-deficient Drosophila have a strongly reduced survival rate after starvation. Our work identifies LUBAC and OTULIN as physiological regulators of AMPK, providing the first mechanism by which M1-linked ubiquitin chains regulate metabolic signalling.

cell biology↗

bioRxiv2020

The retinoic acid receptor drives neuroinflammation and fine tunes the homeostasis of interleukin-17-producing T cells

The vitamin A metabolite retinoic acid (RA) is critical for the maturation and function of the immune system, however, our knowledge regarding its role in gamma delta ({gamma}{delta}) T cells is limited. By specifically inactivating the RA receptor alpha (RAR) in type 3 lymphocytes and using a combination of fetal thymic organ cultures and single-cell RNA-sequencing we found that RA strengthened TCR signaling to limit the embryonic development of interleukin(IL)-17-producing {gamma}{delta} T cells ({gamma}{delta}T17), while at the same time it promoted their survival after birth. In adult mice, RA imposed a multi-level transcriptional program allowing {gamma}{delta}T17 cells to become activated, survive and sense interferon. Consequently, cells with inactive RAR responded poorly to immunization and produced low level of cytokines leading to near disease resistance in the experimental autoimmune encephalomyelitis model. Finally, RA was required for optimal expression of the 4{beta}1 integrin and {gamma}{delta}T17 cell infiltration to the brain. Collectively, these studies suggest that by acting at various stages during the lifetime of {gamma}{delta} T cells, RA supports their normal development, their survival and their ability to respond to inflammatory stimuli.

immunology↗

bioRxiv2019

The neonatal microenvironment programs conventional and intestinal Tbet+ γδT17 cells through the transcription factor STAT5

Interleukin(IL)-17-producing ROR{gamma}t+ {gamma}{delta} T ({gamma}{delta}T17) cells develop in the embryonic thymus and participate in type 3 immune responses. Herein we show that {gamma}{delta}T17 cells rapidly proliferate within neonatal lymph nodes and gut, where upon entry they uniquely upregulate Tbet and co-express IL-17, IL-22 and interferon(IFN) {gamma} in a STAT3 and retinoic acid dependent manner. Neonatal expansion was halted in mice conditionally deficient in STAT5 and its loss resulted in {gamma}{delta}T17 cell depletion from all adult organs. Hyperactive STAT5 mutant mice showed that the STAT5A homologue had a dominant role over STAT5B in promoting {gamma}{delta}T17 cell expansion and downregulating gut-associated Tbet. In contrast, STAT5B preferentially expanded IFN{gamma}-producing {gamma}{delta} populations. Importantly, mice lacking {gamma}{delta}T17 cells due to STAT5 deficiency displayed a profound resistance to experimental autoimmune encephalomyelitis. Our data identify for the first time STAT5 as a key molecular checkpoint allowing {gamma}{delta}T17 cells to pass through a critical neonatal developmental window to acquire tissue-specific characteristics essential for infection and autoimmunity.

immunology↗