Network organization of the human autophagy system

Abstract

Autophagy, the process by which proteins and organelles are sequestered in autophagosomal vesicles and delivered to the lysosome/vacuole for degradation, provides a primary route for turnover of stable and defective cellular proteins. Defects in this system are linked with numerous human diseases. While conserved protein kinase, lipid kinase, and ubiquitin-like (UBL) protein conjugation sub-networks controlling autophagosome formation and cargo recruitment have been defined, our understanding of the global organization of this system is limited. Here, we report a proteomic analysis of the autophagy interaction network (AIN) in human cells under conditions of ongoing (basal) autophagy, revealing a network of 751 interactions among 4 09 candidate interacting proteins with extensive connectivity among sub-networks. Many new AIN components have roles in vesicle trafficking, protein or lipid phosphorylation, and protein ubiquitination, and affect autophagosome number or flux when depleted by RNAi. The six ATG8 orthologs in humans (MAP1LC3/GABARAP proteins) interact with a cohort of 67 proteins, with extensive binding partner overlap between family members, and frequent involvement of a conserved surface on ATG8 proteins known to interact with LC3-interacting regions (LIR) in partner proteins. These studies provide a global view of the mammalian autophagy interaction landscape and a resource for mechanistic analysis of this critical protein homeostasis pathway.

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

“…61 NRBF2 was identified as a protein involved in autophagy, which is present only in the ATG14-containing class III PtdIns3K complex in mammalian cells. [81][82][83]159 The yeast ortholog of NRBF2 is presumed to be Atg38, although there are sequence diversities. 82,160 Likewise, Atg38 is recognized as a component of the Atg14-containing Vps34 complex I in yeast, which is required for the autophagy pathway.…”

AC‐1001 H3 CDR peptide induces apoptosis and signs of autophagy in vitro and exhibits antimetastatic activity in a syngeneic melanoma model

“…Through autophagy, proteins and organelles are sequestered into double membrane vesicles (autophagosomes) and are subsequently delivered to the lysosomes for degradation 44. It is an evolutionary conserved process that occurs in all eukaryotic cells and is characterized by the accumulation of autophagic vesicles 45.…”

Proteomic techniques to probe the ubiquitin landscape

“…Bioinformatic studies are already using the extensive data collected in the large scale studies [132,133]. New studies are now starting to combine the information of ubiquitination with other post-translational modifications like phosphorylation in order to construct more complex networks [134]. New methods for multiplexing samples like the NeuCode technique that is based on differences in the nuclear binding energy allow higher degrees of multiplexing while not increasing the complexity of the sample [48,135].…”