1,721,066 research outputs found
Autophagy, a new determinant of plasma cell differentiation and antibody responses
No full textPlasma cells, the terminal effectors of the B lymphoid lineage, are responsible for the humoral arm of adaptive immunity. Their differentiation from B cells entails a profound cellular reshaping inherently associated with stress. Autophagy is a conserved adaptive cellular strategy recently implicated in differentiation and immunity. We identified a novel autophagic function in plasma cells. Autophagy restricts the expression of the transcriptional repressor Blimp-1 and immunoglobulins through a selective negative control on the endoplasmic reticulum and its stress signaling response, thereby optimizing energy and viability. As a result, autophagy in vivo sustains antibody responses, and is an essential intrinsic determinant of the bone marrow long-lived plasma cell niche. Here, I discuss several immune and biomedical implications, and experimental issues to be addressed in the near future. (C) 2014 Published by Elsevier Ltd
Autophagy in the regulation of protein secretion in immune cells
No full textProtein secretion, a universal cellular feature, plays fundamental roles in innate and adaptive immunity. Indeed, the functional and phenotypic characterization of immune cells (e.g., effector lymphocytes or macrophages) entail quantitative and qualitative analyses of the expression of secretory proteins (e.g., cytokines, antibodies, ligands, and receptors). The conventional secretory pathway starts with an amino-terminal leader peptide driving nascent proteins into the endoplasmic reticulum (ER) for folding, maturation, and transportation to the plasma membrane through the Golgi apparatus. However, proteins lacking a leader sequence exist that are routed to the extracellular space or the plasma membrane through a variety of pathways collectively referred to as unconventional secretion. The field was pioneered in immune models, as epitomized by antibodies and interleukin-1β, paradigms, respectively, of conventional and unconventional protein secretion. Macroautophagy, by convention autophagy, is a fundamental cellular recycling strategy that dispatches unwanted cytoplasmic supramolecular structures to lysosomes upon isolation in double-membrane autophagosomes. Recent evidence heavily implicates autophagy in protein secretion. First, it participates in conventional secretion exerting both positive and negative effects and acting at multiple levels along the secretory pathway. Moreover, autophagy is instrumental to unconventional protein secretion through diverse mechanisms, including the regulation of intracellular inflammatory signaling and the trafficking strategies that allow secretion of leaderless proteins, leading to the recently coined concept of “secretory autophagy.” This chapter will describe the multiple mechanisms whereby autophagy interfaces with both conventional and unconventional protein secretion, with particular focus on their significance in innate and adaptive immunity
Analisi mediante fluorescenza X indotta da luce di sincrotrone su campioni di cenere provenienti dalla combustione di carbone
No full textStudio sperimentale nell'ambito del Contratto RIcerca ENEA - Sapienza n. 2089 Tecniche per il controllo non distruttivo di residui radioattiv
PROTEOSTASIS AS A SIGNALING DEVICE AND THERAPEUTIC TARGET
No full textThe term ‘conformational disorders’ was created recently for the numerous pathological situations due to the accumulation of aberrant proteins (or normal ones in excess). However, defective protein homeostasis (or proteostasis) is not always associatedwith pathology, as it controls the life-span of certain cells and other ‘physiological aging’ signaling processes (in quotes becausehumans are generally reluctant to consider aging a physiological process). As proteotoxicity emerged as the underlying cause of many degenerative diseases, mechanisms controlling proteostasis become crucial pharmacological targets. This chapter summarizes the emerging concepts and some recent results that allow some optimism in the treatment of different severe diseases via the manipulation of proteostasis
Recent advances and future directions in targeting the secretory apparatus in multiple myeloma
No full textMultiple myeloma is a genetically heterogeneous tumour of transformed plasma cells, terminally differentiated effectors of the B cell lineage specialized in producing large amounts of immunoglobulins. The uniquely well-developed secretory apparatus that equips normal and transformed plasma cells with the capacity for high-level protein secretion constitutes a distinctive therapeutic target. In this review we discuss how fundamental cellular processes, such as the unfolded protein response (UPR), endoplasmic reticulum (ER)-associated degradation and autophagy, maintain intracellular protein homeostasis (proteostasis) and regulate plasma cell ontogenyand malignancy. We summarize our current understanding of the cellular effects of proteasome inhibitors and the molecular bases of resistance to them. Furthermore, we discuss how improvements in our understanding of the secretory apparatus and of the complex interactions between intracellular protein synthesis and degradation pathways can disclose novel drug targets for multiple myeloma, defining a paradigm of general interest forcancer biologyand disorders of altered proteostasis
Ipotesi di fattibilità di un tomografo per il controllo di qualità di matrici cementizie inglobanti residui radioattivi a bassa e media attività
No full textProgetto di un sistema di tomografia Single Pencil Beam per rifiuti radioattivi condizionat
Managing and exploiting stress in the antibody factory
No full textAbstractLike us, our cells have evolved strategies to cope with, and sometimes utilize, stress. Molecular analyses of plasma cell biogenesis, lifestyle and death suggest that protein synthesis-dependent stress is utilised to integrate differentiation, function and lifespan control. Plasma cells are short-lived professional secretory cells, each of them capable of releasing several thousands antibodies per second. Their differentiation from B lymphocytes entails the spectacular enlargement of the endoplasmic reticulum (ER), finalized to sustain massive Ig production. Nonetheless, symptoms of ER stress are evident, and the UPR-related transcription factor XBP-1 is essential for differentiation. Surprisingly, the development of such an efficient factory is matched by a decrease in proteasomes. The unbalanced load/capacity ratio leads to accumulation of polyubiquitinated molecules and predisposes plasma cells to apoptosis. Exuberant antibody secretion imposes considerable stress on metabolic and redox homeostasis. Collectively, these stressful conditions may link plasma cell death to antibody production, providing a molecular counter for secreted molecules, as well as an explanation for the peculiar sensitivity of myeloma cells towards proteasome inhibitors
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