Amino acid control of protein degradation in normal and leukemic human lymphocytes

Seglen, Per Ottar; Munthe‐Kaas, Amy C.; Dybedal, Mary Ann S.

doi:10.1016/0014-4827(84)90773-0

Cited by 14 publications

(7 citation statements)

References 24 publications

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“…Nevertheless, several tumour cell lines retain a high autophagic capacity. Starvation induced autophagy has been observed in cervical cancer HeLa cells, and in lymphocytes isolated from patients with chronic lymphocytic leukemia [113,114]. These findings strongly suggest that autophagy may play dual roles in cancer progression.…”

Section: Autophagy In Cancermentioning

confidence: 54%

Autophagy: molecular mechanisms, physiological functions and relevance in human pathology

Mariño

López-Otı́n

2004

CMLS, Cell. Mol. Life Sci.

210

149

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Autophagy is a degradative mechanism mainly involved in the recycling and turnover of cytoplasmic constituents from eukaryotic cells. Over the last years, yeast genetic screens have considerably increased our knowledge about the molecular mechanisms of autophagy, and a number of genes involved in fundamental steps of the autophagic pathway have been identified. Most of these autophagy genes are present in higher eukaryotes indicating that this process has been evolutionarily conserved. In yeast, autophagy is mainly involved in adaptation to starvation, but in multicellular organisms this route has emerged as a multifunctional pathway involved in a variety of additional processes such as programmed cell death, removal of damaged organelles and development of different tissue-specific functions. Furthermore, autophagy is associated with a growing number of pathological conditions, including cancer, myopathies and neurodegenerative disorders. The physiological and pathological roles of autophagy, as well as the molecular mechanisms underlying this multifunctional pathway, are discussed in this review.

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Section: Autophagy In Cancermentioning

confidence: 54%

Autophagy: molecular mechanisms, physiological functions and relevance in human pathology

Mariño

López-Otı́n

2004

CMLS, Cell. Mol. Life Sci.

210

149

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“…[14][15][16][17] To examine the role of autophagy in ALIS formation, we first treated HeLa cells with 3-methyladenine (3MA; inhibitor of autophagy pathway). 33 In contrast to cells treated with epoxomicin, the presence of 3MA alone was sufficient to induce ALIS formation in HeLa cells. ALIS appeared in ~20% of 3MA-treated cells over the course of the experiment, compared to control levels ranging from 0-3% (Fig.…”

Section: Resultsmentioning

confidence: 88%

ALIS are Stress-Induced Protein Storage Compartments for Substrates of the Proteasome and Autophagy

Szeto

Kaniuk²,

Canadien³

et al. 2006

Autophagy

184

241

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Misfolded proteins can be directed into cytoplasmic aggregates such as aggresomes and dendritic cell aggresome-like induced structures (DALIS). DALIS were originally identified in lipopolysaccharide-stimulated dendritic cells and act as storage compartments for polyubiquitinated Defective Ribosomal Products (DRiPs) prior to their clearance by the proteasome. Here we demonstrate that ubiquitinated protein aggregates that are similar to DALIS, and not related to aggresomes, can be observed in several cell types in response to stress, including oxidative stress, transfection, and starvation. Significantly, both immune and nonimmune cells could form these aggresome-like induced structures (ALIS). Protein synthesis was essential for ALIS formation in response to oxidative stress, indicating that DRiP formation was required. Furthermore, puromycin, which increases DRiP formation, was sufficient to induce ALIS formation. Inhibition of either proteasomes or of autophagy interfered with ALIS clearance in puromycin treated cells. Autophagy inhibition enhanced ALIS formation under a variety of stress conditions. During starvation, ALIS formation in autophagy-deficient cells was only partially inhibited by protein synthesis inhibitors, indicating that both long-lived proteins and DRiPs can be targeted to ALIS. Together, these findings demonstrate that ALIS act as generalized stress-induced protein storage compartments for substrates of the proteasome and autophagy.

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“…In addition, autophagy is involved in tumor development (36,37). Starvation-induced autophagy has been observed, for example, in lymphocytes isolated from patients with chronic lymphocytic leukemia (38). This finding might Breakdown products were quantified by their peak heights in the RP-HPLC chromatogram.…”

Section: Discussionmentioning

confidence: 84%

Autophagy promotes MHC class II presentation of peptides from intracellular source proteins

Dengjel

Schoor

Fischer

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

570

517

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MHC-peptide complexes mediate key functions in adaptive immunity. In a classical view, MHC-I molecules present peptides from intracellular source proteins, whereas MHC-II molecules present antigenic peptides from exogenous and membrane proteins. Nevertheless, substantial crosstalk between these two pathways has been observed. We investigated the influence of autophagy on the MHC-II ligandome and demonstrated that peptide presentation is altered considerably upon induction of autophagy. The presentation of peptides from intracellular and lysosomal source proteins was strongly increased on MHC-II in contrast with peptides from membrane and secreted proteins. In addition, autophagy influenced the MHC-II antigen-processing machinery. Our study illustrates a profound influence of autophagy on the class II peptide repertoire and suggests that this finding has implications for the regulation of CD4 ؉ T cell-mediated processes.antigen processing ͉ lysosomal proteases ͉ T helper cells P eptides of foreign and self proteins are presented on MHC-I and MHC-II molecules at the cell surface and can be recognized by CD8ϩ and CD4 ϩ T lymphocytes, respectively (1, 2). From a classical point of view, MHC-I molecules present antigenic peptides derived from intracellular proteins, whereas MHC-II molecules do so for exogenous and membrane proteins (3). This phenomenon is reflected in the two major cellular breakdown pathways for proteins: proteasomal degradation, particularly relevant to the generation of MHC-I peptides (4), and degradation by the endosomal͞lysosomal system, which is responsible for the processing of MHC-II peptides (5). However, the separation of these distinct pools of source proteins is less stringent than originally believed. It is now well established that MHC-I molecules are able to present peptides derived from exogenous antigens (Ag) by a process known as cross presentation (6). On the other hand, intracellular proteins can be presented by MHC-II molecules (7,8), even though the underlying processes are less clear. It has been recently shown that peptides from cytosolic model proteins can be presented on MHC-II molecules through autophagy (9-11). Autophagy plays a role in the endosomal͞lysosomal degradation pathway and is responsible for feeding intracellular components into this pathway. It is thought to be required for normal turnover of cellular components, particularly in response to starvation (12). Against this background, we hypothesized that autophagy might mediate MHC-II presentation of intracellular Ag, meaning the contents of a cell contained within the plasma membrane, excluding large vacuoles and secretory or ingested material (Gene Ontology classifications), in general. Therefore, we performed a detailed characterization of the MHC-II ligand repertoire (ligandome) presented at the cell surface under normal conditions and after increased autophagy, leading to a comprehensive overall picture of changes in peptide processing and presentation. Materials and MethodsCell Culture and Autophagy Inducti...

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Amino acid control of protein degradation in normal and leukemic human lymphocytes

Cited by 14 publications

References 24 publications

Autophagy: molecular mechanisms, physiological functions and relevance in human pathology

Autophagy: molecular mechanisms, physiological functions and relevance in human pathology

ALIS are Stress-Induced Protein Storage Compartments for Substrates of the Proteasome and Autophagy

Autophagy promotes MHC class II presentation of peptides from intracellular source proteins

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