Catálogo de publicaciones - revistas

<jats:sec> <jats:title>BACKGROUND</jats:title> <jats:p>Proteins are synthesized on ribosomes as linear chains of amino acids and must fold into unique three-dimensional structures to fulfill their biological functions. Protein folding is intrinsically error-prone, and how it is accomplished efficiently represents a problem of great biological and medical importance. During folding, the nascent polypeptide must navigate a complex energy landscape. As a result, misfolded molecules may accumulate that expose hydrophobic amino acid residues and thus are in danger of forming potentially toxic aggregates. To ensure efficient folding and prevent aggregation, cells in all domains of life express various classes of proteins called molecular chaperones. These proteins receive the nascent polypeptide chain emerging from the ribosome and guide it along a productive folding pathway. Because proteins are structurally dynamic, constant surveillance of the proteome by an integrated network of chaperones and protein degradation machineries, the proteostasis network (PN), is required to maintain protein homeostasis in a range of external and endogenous stress conditions.</jats:p> </jats:sec> <jats:sec> <jats:title>ADVANCES</jats:title> <jats:p>Over the past decade, we have gained substantial new insight into the overall behavior of the PN and the molecular mechanics of its components. Advances in structural biology and biophysical approaches have allowed chaperone mechanisms to be interrogated at an unprecedented level of detail. Recent work has provided fascinating insight into the process of protein folding on the ribosome and revealed how highly allosteric chaperones such as the heat shock protein 70 (Hsp70), Hsp90, and chaperonin systems modulate the folding energy landscapes of their protein clients. Studies of chaperone systems from bacteria and eukaryotes have revealed common principles underlying the organization of chaperone networks in different domains of life. Recently, we have begun to appreciate the relative complexity of eukaryotic chaperones and are starting to understand how eukaryotes deal with the challenge of folding a large proteome enriched in multidomain proteins. At the cellular level, the response of the PN to conformational stress, aging, and diseases of aberrant protein folding has been an area of intense investigation. Importantly, the capacity of the PN declines during aging and this leads to dysfunction of specific cell types and tissues, rendering the organism susceptible to chronic diseases. Among these, neurodegenerative syndromes associated with protein aggregation are increasingly prevalent in the aging human population. Notably, the accumulation of toxic protein aggregates is both a consequence and a cause of PN decline, driving a vicious cycle that ultimately leads to proteostasis collapse.</jats:p> </jats:sec> <jats:sec> <jats:title>OUTLOOK</jats:title> <jats:p>A new view of protein folding is emerging, whereby the energy landscapes that proteins navigate during folding in vivo may differ substantially from those observed during refolding in vitro. From the ribosome through to the major chaperone systems, the nascent protein interacts with factors that modulate its folding pathway. Future work should focus on obtaining the high-resolution structural and kinetic information necessary to define the pathways of protein folding during translation, and in association with molecular chaperones. Organisms have evolved various mechanisms to deal with misfolded and aggregated proteins to maintain proteostasis. It is becoming increasingly clear that besides removing these proteins by degradation, cells also strategically sequester them into transient or stable aggregates, often in defined cellular locations. Much remains to be understood about how this cellular decision-making occurs at a molecular level and how dysregulation of these mechanisms leads to proteotoxicity. From a medical perspective, the intimate relationship between proteostasis and disease, aging, and neurodegeneration makes components of the PN logical drug targets, with the goal of promoting healthy aging. Pharmacological manipulation of the PN will require a detailed understanding of how the network responds to perturbation and how its different components cooperate.</jats:p> <jats:fig fig-type="figure" orientation="portrait" position="float"> <jats:caption> <jats:title>Molecular chaperones are key players in the cellular proteostasis network and serve to maintain a balanced proteome.</jats:title> <jats:p>They promote the folding of newly synthesized proteins, function in conformational maintenance, and prevent potentially toxic off-pathway aggregation. Chaperones also cooperate with other components of the proteostasis network, such as the proteasome system and autophagy, in the removal of terminally misfolded and aggregated proteins through proteolytic degradation.</jats:p> </jats:caption> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" orientation="portrait" position="float" xlink:href="353_aac4354_Fa.jpeg" /> </jats:fig> </jats:sec>

<jats:sec> <jats:title>INTRODUCTION</jats:title> <jats:p>Regenerative therapies based on cell replacement hold promise for the treatment of a range of age-related degenerative diseases but are limited by unfavorable microenvironments in degenerating tissues. A promising strategy to improve success is to harness endogenous repair mechanisms that promote tissue integrity and function. Innate immune cells are central to such repair mechanisms because they coordinate local and systemic responses to tissue injury by secreting inflammatory and anti-inflammatory signals in a context-dependent manner. A proper balance between these opposing phenotypes of innate immune cells is essential for efficient tissue repair, and immune modulation may be an effective way to promote repair and enhance regenerative therapies. Here, we identified a new evolutionarily conserved immune modulatory function for mesencephalic astrocyte-derived neurotrophic factor (MANF) that biases immune cells toward an anti-inflammatory phenotype, thereby promoting tissue repair in both vertebrates and invertebrates and enhancing retinal regenerative therapy.</jats:p> </jats:sec> <jats:sec> <jats:title>RATIONALE</jats:title> <jats:p> In <jats:italic>Drosophila</jats:italic> , interactions between damaged tissues and hemocytes are essential for tissue repair. We used this model to identify immune cell–derived factors with immune modulatory activity that promote tissue repair after retinal injury. The identification of MANF as such a factor prompted us to test its role in mammalian retinal repair and ask whether its immune modulatory activity helped cell replacement therapies in degenerating retinas. </jats:p> </jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p> Using a combination of transcriptome analysis and genetic studies, we identified MANF as a hemocyte-derived factor that is induced by platelet-derived growth factor (PDGF)– and vascular endothelial growth factor (VEGF)–related factor 1 (Pvf-1)/PDGF- and VEGF-receptor related (PvR) signaling. MANF was necessary and sufficient to promote retinal repair after ultraviolet-light–induced retinal injury in <jats:italic>Drosophila.</jats:italic> MANF also had an autocrine immune-modulatory function in fly hemocytes, which was necessary for its tissue repair–promoting activity. This regulation and function of MANF was evolutionarily conserved: Mouse photoreceptors expressed PDGF-A (a Pvf-1 homolog) in response to damage signals, which promoted MANF expression in innate immune cells. This PDGF-A/MANF signaling cascade was required to limit photoreceptor apoptosis in the retina. Exogenously supplied recombinant MANF protected photoreceptors in several paradigms of retinal injury and degeneration. As in flies, this prorepair function was associated with alternative activation of macrophages and microglia in the retina. Ablation of CD11b <jats:sup>+</jats:sup> immune cells and deletion of Cx3Cr1, a chemokine receptor required for MANF-induced alternative activation, prevented MANF-induced repair. Thus, the protective effects of MANF in retinal injury rely on its immune modulatory activity. Finally, MANF supplementation to photoreceptors transplanted into congenitally blind mice increased integration efficiency and accelerated and improved visual function recovery. </jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUSION</jats:title> <jats:p>Combining genetic studies in invertebrates and vertebrates has rapidly identified factors with promising therapeutic potential. Immune modulation is a promising strategy to optimize regenerative therapies. With its conserved immune modulatory function, MANF is a particularly promising molecule that is likely to be useful for the treatment of inflammatory conditions in many different disease contexts.</jats:p> <jats:fig fig-type="figure" orientation="portrait" position="float"> <jats:caption> <jats:title>MANF in retinal repair.</jats:title> <jats:p> In <jats:italic>Drosophila</jats:italic> (left) or mouse (right), the damaged retina secretes Pvf-1/PDGF-A, which acts on innate immune cells. MANF derived from innate immune cells (and other sources) promotes phenotypic changes in immune cells as part of a mechanism required for tissue repair. Therapeutically, MANF supplementation can delay retinal degeneration and improve the success of cell-replacement regenerative therapies in the retina. </jats:p> </jats:caption> <jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" orientation="portrait" position="float" xlink:href="353_aaf3646_Fa.jpeg" /> </jats:fig> </jats:sec>