Ubiquitylation in immune disorders and cancer: from molecular mechanisms to therapeutic implications

Conjugation of ubiquitin to proteins (ubiquitylation) has emerged to be one of the most crucial post-translational modifications controlling virtually all cellular processes. What was once regarded as a mere signal for protein degradation has turned out to be a major regulator of molecular signalling networks. Deregulation of ubiquitin signalling is closely associated with various human pathologies. Here, we summarize the current knowledge of ubiquitin signalling in immune deficiencies and cancer as well as the available therapeutic strategies targeting the ubiquitin system in combating these pathogenic conditions

Ubiquitylation in immune disorders and cancer: from molecular mechanisms to therapeutic implications

Conjugation of ubiquitin to proteins (ubiquitylation) has emerged to be one of the most crucial post-translational modifications controlling virtually all cellular processes. What was once regarded as a mere signal for protein degradation has turned out to be a major regulator of molecular signalling networks. Deregulation of ubiquitin signalling is closely associated with various human pathologies. Here, we summarize the current knowledge of ubiquitin signalling in immune deficiencies and cancer as well as the available therapeutic strategies targeting the ubiquitin system in combating these pathogenic conditions

An ultrasensitive sorting mechanism for EGF receptor endocytosis

Background The EGF receptor has been shown to internalize via clathrin-independent endocytosis (CIE) in a ligand concentration dependent manner. From a modeling point of view, this resembles an ultrasensitive response, which is the ability of signaling networks to suppress a response for low input values and to increase to a pre-defined level for inputs exceeding a certain threshold. Several mechanisms to generate this behaviour have been described theoretically, the underlying assumptions of which, however, have not been experimentally demonstrated for the EGF receptor internalization network. Results Here, we present a mathematical model of receptor sorting into alternative pathways that explains the EGF-concentration dependent response of CIE. The described mechanism involves a saturation effect of the dominant clathrin-dependent endocytosis pathway and implies distinct steady-states into which the system is forced for low vs high EGF stimulations. The model is minimal since no experimentally unjustified reactions or parameter assumptions are imposed. We demonstrate the robustness of the sorting effect for large parameter variations and give an analytic derivation for alternative steady-states that are reached. Further, we describe extensibility of the model to more than two pathways which might play a role in contexts other than receptor internalization. Conclusions Our main result is that a scenario where different endocytosis routes consume the same form of receptor corroborates the observation of a clear-cut, stimulus dependent sorting. This is especially important since a receptor modification discriminating between the pathways has not been found. The model is not restricted to EGF receptor internalization and might account for ultrasensitivity in other cellular contexts

CYLD in Ubiquitin Signaling and Tumor Pathogenesis

Absence of CYLD, which encodes a deubiquitinating enzyme, causes an inherited disease characterized by benign skin tumors. In this issue of Cell, Massoumi et al. (2006) show that CYLD deubiquitinates the coactivator Bcl-3, thereby preventing its translocation into the nucleus, where it normally interacts with NF-κB and activates transcription of proliferation genes in response to growth signals

ER remodeling via ER-phagy

The endoplasmic reticulum (ER) is a hotspot for many essential cellular functions. The ER membrane is highly dynamic, which affects many cellular processes that take place within the ER. One such process is ER-phagy, a selective degradation of ER fragments (including membranes and luminal content), which serves to preserve the size of ER while adapting its morphology under basal and stress conditions. In order to be degraded, the ER undergoes selective fragmentation facilitated by specialized ER-shaping proteins that also act as ER-phagy receptors. Their ability to sense and induce membrane curvature, as well as to bridge the ER with autophagy machinery, allows for a successful ER fragmentation and delivery of these fragments to the lysosome for degradation and recycling. In this review, we provide insights into ER-phagy from the perspective of membrane remodeling. We highlight the importance of ER membrane dynamics during ER-phagy and emphasize how its dysregulation reflects on human physiology and pathology

Deciphering Functions of Branched Ubiquitin Chains

The anaphase-promoting complex/cyclosome targets proteins for degradation by catalyzing homotypic ubiquitin chains of different linkage types. In this issue of Cell, Meyer and Rape diversify the degradation signals by demonstrating that the APC/C and its cognate E2 conjugating enzymes enhance the rate of substrate degradation by decorating them with branched Lys11 and Lys48 ubiquitin chains

Integration of INS, GPS, Magnetometer and Barometer for Improving Accuracy Navigation of the Vehicle

This paper describes integrated navigation system that is based on a low cost inertial sensor, global positioning system (GPS) receiver, magnetometer and a barometer, in order to improve accuracy of complete attitude and navigation solution. The main advantage of integration consists in availability of reliable navigation parameters during the intervals of absence of GPS data. The magnetometer and the barometer are applied for the attitude calibration and vertical channel stabilization, respectively. The acceptable accuracy of inertial navigation system (INS) is achieved by the proper damping of INS errors. The integration is made by the implementation of an extended Kalman filter (EKF) with control signal that is designed appropriate for low accuracy sensors noise characteristics. The analysis of integrated navigation system performances is made experimentally and the results show that integrated navigation system provides continuous and reliable navigation solutions.Defence Science Journal, 2013, 63(5), pp.451-455, DOI:http://dx.doi.org/10.14429/dsj.63.453

Some Insurance Options on Stochastic Drawdowns

Insurance and options have been often used by investors to protect themselves from market crashes and significant financial losses. Thanks to its desired features, drawdowns can be a very useful tool in the marketplace, allowing investors to protect against the downside risks which commonly occur in the marketplace. Several insurance products are proposed via including protection against drawdown sizes, speed of market crash and frequency of drawdowns. We also design a knock-in drawdown option with generalized payoffs. In this thesis, we explore the probabilistic approach to drawdowns and use the technique of Laplace transform to find the fair market price of the designed insurances/options. Their connections with the existing models are discussed, and numerical results are then demonstrated as well as the sensitivity tests

The role of OTULIN in skin inflammation and cell death

The skin epithelium provides a physical and immunologically active multilayered barrier that protects the body from environmental factors and mediates cellular immune responses. Especially mechanisms regulating the cell survival and cell death of epidermal keratinocytes play a crucial role in maintaining tissue homeostasis. Inflammatory and cell death signalling is tightly controlled by linear ubiquitination, mediated via the E3 ligase Linear Ubiquitin Assembly Complex (LUBAC) to initiate innate immune responses. LUBAC itself is controlled by OTU deubiquitinase with linear specificity (OTULIN), a deubiquitinating enzyme that specifically degrades linear ubiquitin chains. Mouse model studies suggested that OTULIN deficiency results in loss of LUBAC components and cell death-mediated inflammation. Interestingly, mutations in the gene encoding OTULIN cause the OTULIN-related autoinflammatory syndrome (ORAS), a human genetic disease presented with complex pathological features and systemic inflammation affecting multiple organs, including the skin. The role of OTULIN in regulating skin homeostasis, inflammation and cell death is poorly understood and remains to be elucidated. The aim of this study was to investigate the biological function of OTULIN in the skin and to unravel the underlying cellular processes. The results acquired in this thesis reveal that OTULIN prevents skin inflammation by inhibiting keratinocyte necroptosis. In detail, deleting OTULIN in the mouse epidermis causes skin lesions that develop in different parts of the skin, including the tail. Those lesions resemble papilloma-like structures and are displayed with an inflammatory gene expression profile. Our genetic studies demonstrate that this skin pathology is driven by TNFR1 mediated RIPK1 kinase-dependent cell death. Furthermore, RIPK3 and MLKL deficiency strongly protect mice lacking OTULIN in keratinocytes from skin inflammation, thereby identifying necroptosis as a key driver, whereas FADD-dependent apoptosis plays a minor role in the skin disease development. Additionally, MyD88 deficiency strongly delayed and ameliorated skin pathology, implying that microbiota-dependent stimuli contribute to the pathogenesis in OTULINE-KO mice. Taken together, the data presented in this study uncover a key role for OTULIN in the epidermis in preventing cell death and inflammation to maintain skin homeostasis