A new class of ubiquitin-Atg8 receptors involved in selective autophagy and polyQ protein clearance

Selective ubiquitin-dependent autophagy mediates the disposal of superfluous cellular structures and clears cells of protein aggregates such as polyQ proteins linked to Huntington disease. Crucial selectivity factors of this pathway are ubiquitin-Atg8 receptors such as human SQSTM1/p62, which recognize ubiquitinated cargoes and deliver them to phagophores for degradation. Contrasting previous beliefs, we recently showed that ubiquitin-dependent autophagy is not restricted to higher eukaryotes but also exists in yeast with Cue5, harboring a ubiquitin-binding CUE domain, being a ubiquitin-Atg8 receptor. Notably, the human CUE domain protein TOLLIP is functionally similar to yeast Cue5, indicating that Cue5/TOLLIP (CUET) proteins represent a new and conserved class of autophagy receptors. Remarkably, both Cue5 in yeast and TOLLIP in human cells mediate efficient clearance of aggregation-prone polyQ proteins derived from human HTT/huntingtin. Indeed, TOLLIP is potentially more potent in polyQ clearance than SQSTM1/p62 in HeLa cells, suggesting that TOLLIP, also implicated in innate immunity, may be significant for human health and disease.     

Mechanisms of lysosomal positioning and movement

Lysosomes are highly dynamic organelles that can move rapidly throughout the cell. They distribute in a rather immobile pool located around the microtubule‐organizing center in a “cloud,” and a highly dynamic pool in the cell periphery. Their spatiotemporal characteristics allow them to carry out multiple biological functions, such as cargo degradation, antigen presentation and plasma membrane repair. Therefore, it is not surprising that lysosomal dysfunction underlies various diseases, including cancer, neurodegenerative and autoimmune diseases. In most of these biological events, the involvement of lysosomes is dependent on their ability to move throughout the cytoplasm, to find and fuse to the correct compartments to receive and deliver substrates for further handling. These dynamics are orchestrated by motor proteins moving along cytoskeletal components. The complexity of the mechanisms responsible for controlling lysosomal transport has recently been appreciated and has yielded novel insights into interorganellar communication, as well as lipid‐protein interplay. In this review, we discuss the current understanding of the mechanisms of lysosomal transport and the molecular machineries that control this mobility.      

Systematically defining selective autophagy receptor-specific cargo using autophagosome content profiling

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A new class of ubiquitin-Atg8 receptors involved in selective autophagy and polyQ protein clearance

Selective ubiquitin-dependent autophagy mediates the disposal of superfluous cellular structures and clears cells of protein aggregates such as polyQ proteins linked to Huntington disease. Crucial selectivity factors of this pathway are ubiquitin-Atg8 receptors such as human SQSTM1/p62, which recognize ubiquitinated cargoes and deliver them to phagophores for degradation. Contrasting previous beliefs, we recently showed that ubiquitin-dependent autophagy is not restricted to higher eukaryotes but also exists in yeast with Cue5, harboring a ubiquitin-binding CUE domain, being a ubiquitin-Atg8 receptor. Notably, the human CUE domain protein TOLLIP is functionally similar to yeast Cue5, indicating that Cue5/TOLLIP (CUET) proteins represent a new and conserved class of autophagy receptors. Remarkably, both Cue5 in yeast and TOLLIP in human cells mediate efficient clearance of aggregation-prone polyQ proteins derived from human HTT/huntingtin. Indeed, TOLLIP is potentially more potent in polyQ clearance than SQSTM1/p62 in HeLa cells, suggesting that TOLLIP, also implicated in innate immunity, may be significant for human health and disease.     

Procyanidin dimer B2-mediated IRAK-M induction negatively regulates TLR4 signaling in macrophages

Polyphenolic compounds have been found to possess a wide range of physiological activities that may contribute to their beneficial effects against inflammation-related diseases; however, the molecular mechanisms underlying this anti-inflammatory activity are not completely characterized, and many features remain to be elucidated. In this study, we investigated the molecular basis for the down-regulation of toll-like receptor 4 (TLR4) signal transduction by procyanidin dimer B2 (Pro B2) in macrophages. Pro B2 markedly elevated the expression of the interleukin (IL)-1 receptor-associated kinase (IRAK)-M protein, a negative regulator of TLR signaling. Lipopolysaccharide (LPS)-induced expression of cell surface molecules (CD80, CD86, and MHC class I/II) and production of pro-inflammatory cytokines (tumor necrosis factor-α, IL-1β, IL-6, and IL-12p70) were inhibited by Pro B2, and this action was prevented by IRAK-M silencing. In addition, Pro B2-treated macrophages inhibited LPS-induced activation of mitogen-activated protein kinases such as extracellular signal-regulated kinase 1/2, p38, and c-Jun N-terminal kinase and the translocation of nuclear factor κB and p65 through IRAK-M. We also found that Pro B2-treated macrophages inactivated naïve T cells by inhibiting LPS-induced interferon-γ and IL-2 secretion through IRAK-M. These novel findings provide new insights into the understanding of negative regulatory mechanisms of the TLR4 signaling pathway and the immune-pharmacological role of Pro B2 in the immune response against the development and progression of many chronic diseases.