Advances in biological regulation最新文献

The intricate interplay between lamins and chromatin underpins the structural integrity and functional organization of the eukaryotic nucleus. Lamins, type V intermediate filament proteins, form a robust meshwork beneath the inner nuclear membrane that is crucial for sustaining nuclear architecture through interactions with lamin-associated domains (LADs). LADs are predominantly heterochromatic regions in which compacted chromatin is enriched at the nuclear periphery, interacting with lamins and lamin-associated proteins. Disruptions of these interactions are implicated in a spectrum of diseases, including laminopathies, cancer, and age-related pathologies, highlighting the importance of lamin-LAD interactions. Thus, a detailed understanding of lamin-chromatin interactions may provide new insights into chromatin organization and shed light on the mechanism behind certain disease states. Here, we discuss the current state of knowledge of lamin-chromatin interactions from a biochemical and structural point of view.

Fructose 1,6-bisphosphatase (FBP) is a regulatory enzyme of gluconeogenesis that also influences in a non-catalytic manner - via protein-protein interactions - cell cycle-dependent events, mitochondria biogenesis and polarization, synaptic plasticity and even cancer progression. FBP reduces glycolytic capacity of cells via blocking HIF-1α transcriptional activity and modulating NF-κB action, and influences oxidative metabolism by binding to c-MYC. Because FBP limits the energy-producing potential of cells and because a reduction of FBP amounts is observed in cancer cells, FBP is considered to be an anti-oncogenic protein. This is supported by the observation that cancer cells overexpress aldolase A (ALDOA), a pro-oncogenic protein that can bind to FBP and potentially block its anti-oncogenic activity. Interestingly, only the muscle isozyme of FBP (FBP2) interacts strongly with ALDOA, whereas the binding of the liver isozyme (FBP1) to ALDOA is more than an order of magnitude weaker. Here, we briefly review the most important evidence supporting the anti-oncogenic function of FBP and discuss what structural properties of the two FBP isozymes allow FBP2, rather than FBP1, to exert more flexible anticancer functions.

PITPNC1 was the last of the PITPs to be identified and has been characterized as a binding protein for phosphatidylinositol and phosphatidate. In mammals, PITPNC1 is expressed as two splice variants whilst in zebrafish is expressed from two separate genes. The two splice variants have different expression profiles with the long splice variant having a prominent role in the brain. Several physiological functions have been identified including neuronal and metabolic functions. PITPNC1 also plays a significant role in cancer and has been identified as a risk factor in type 2 diabetes. Here, we review our current understanding of PITPNC1 in cell physiology and pathology.

The transcription factor NF-κB plays a critical role in the control of innate and adaptive immunity and inflammation. Several recent studies have demonstrated that the mutation of different splicing factor genes, including SF3B1, SRSF2 and U2AF1, in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) result in hyperactive NF-κB signaling through the aberrant splicing of different target genes. The presence of U2AF1 and SF3B1 mutations in the bone marrow cells of MDS and AML patients induces oncogenic isoforms of the target gene IRAK4, leading to hyperactivation of NF-κB signaling and an increase in the fitness of leukemic stem and progenitor cells (LSPCs). The potent IRAK4 inhibitor CA-4948 has shown efficacy in both pre-clinical studies and MDS clinical trials, with splicing factor mutant patients showing the higher response rates. Emerging data has, however, revealed that co-targeting of IRAK4 and its paralog IRAK1 is required to maximally suppress LSPC function in vitro and in vivo by inducing cellular differentiation. These findings provide a link between the presence of the commonly mutated splicing factor genes and activation of innate immune signaling pathways in myeloid malignancies and have important implications for targeted therapy in these disorders.

Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA). Mammalian DGK comprise ten isozymes (α-κ) that regulate a wide variety of physiological and pathological events. Recently, we revealed that DGK isozymes use saturated fatty acid (SFA)/monosaturated fatty acid (MUFA)-containing and docosahexaenoic acid (22:6)-containing DG species, but not phosphatidylinositol (PI) turnover-derived 18:0/20:4-DG. For example, DGKδ, which is involved in the pathogenesis of type 2 diabetes, preferentially uses SFA/MUFA-containing DG species, such as 16:0/16:0- and 16:0/18:1-DG species, in high glucose-stimulated skeletal muscle cells. Moreover, DGKδ, which destabilizes the serotonin transporter (SERT) and regulates the serotonergic system in the brain, primarily generates 18:0/22:6-PA. Furthermore, 16:0/16:0-PA is produced by DGKζ in Neuro-2a cells during neuronal differentiation. We searched for SFA/MUFA-PA- and 18:0/22:6-PA-selective binding proteins (candidate downstream targets of DGKδ) and found that SFA/MUFA-PA binds to and activates the creatine kinase muscle type, an energy-metabolizing enzyme, and that 18:0/22:6-PA interacts with and activates Praja-1, an E3 ubiquitin ligase acting on SERT, and synaptojanin-1, a key player in the synaptic vesicle cycle. Next, we searched for SFA/MUFA-DG-generating enzymes upstream of DGKδ. We found that sphingomyelin synthase (SMS)1, SMS2, and SMS-related protein (SMSr) commonly act as phosphatidylcholine (PC)-phospholipase C (PLC) and phosphatidylethanolamine (PE)-PLC, generating SFA/MUFA-DG species, in addition to SMS and ceramide phosphoethanolamine synthase. Moreover, the orphan phosphatase PHOSPHO1 showed PC- and PE-PLC activities that produced SFA/MUFA-DG. Although PC- and PE-PLC activities were first described 70-35 years ago, their proteins and genes were not identified for a long time. We found that DGKδ interacts with SMSr and PHOSPHO1, and that DGKζ binds to SMS1 and SMSr. Taken together, these results strongly suggest that there are previously unrecognized signal transduction pathways that include DGK isozymes and generate and utilize SFA/MUFA-DG/PA or 18:0/22:6-DG/PA but not PI-turnover-derived 18:0/20:4-DG/PA.