bims-apauto 2023-04-23 papers

Issue of 2023–04–23
four papers selected by
Su Hyun Lee, Harvard University

Nat Commun. 2023 04 15. 14(1): 2160

Trim-Away ubiquitinates and degrades lysine-less and N-terminally acetylated substrates.

Leo Kiss, Tyler Rhinesmith, Jakub Luptak, Claire F Dickson, Jonas Weidenhausen, Shannon Smyly, Ji-Chun Yang, Sarah L Maslen, Irmgard Sinning, David Neuhaus, Dean Clift, Leo C James.

TRIM proteins are the largest family of E3 ligases in mammals. They include the intracellular antibody receptor TRIM21, which is responsible for mediating targeted protein degradation during Trim-Away. Despite their importance, the ubiquitination mechanism of TRIM ligases has remained elusive. Here we show that while Trim-Away activation results in ubiquitination of both ligase and substrate, ligase ubiquitination is not required for substrate degradation. N-terminal TRIM21 RING ubiquitination by the E2 Ube2W can be inhibited by N-terminal acetylation, but this doesn't prevent substrate ubiquitination nor degradation. Instead, uncoupling ligase and substrate degradation prevents ligase recycling and extends functional persistence in cells. Further, Trim-Away degrades substrates irrespective of whether they contain lysines or are N-terminally acetylated, which may explain the ability of TRIM21 to counteract fast-evolving pathogens and degrade diverse substrates.

DOI: https://doi.org/10.1038/s41467-023-37504-x

Autophagy. 2023 Apr 16. 1-5

Ubiquitin-binding autophagic receptors in yeast: Cue5 and beyond.

Theresah Nana Ama Mensah, Ankit Shroff, Taras Y Nazarko.

The selectivity in selective macroautophagy/autophagy pathways is achieved via selective autophagy receptors (SARs) - proteins that bind a ligand on the substrate to be degraded and an Atg8-family protein on the growing autophagic membrane, phagophore, effectively bridging them. In mammals, the most common ligand of SARs is ubiquitin, a small protein modifier that tags substrates for their preferential degradation by autophagy. Consequently, most common SARs are ubiquitin-binding SARs, such as SQSTM1/p62 (sequestosome 1). Surprisingly, there is only one SAR of this type in yeast - Cue5, which acts as the receptor for aggrephagy and proteaphagy - pathways that remove ubiquitinated protein aggregates and proteasomes, respectively. However, recent studies described ubiquitin-dependent autophagic pathways that do not require Cue5, e.g. the stationary phase lipophagy for lipid droplets or nitrogen starvation-induced mitophagy for mitochondria. What is the role of ubiquitin in these pathways? Here, we propose that ubiquitinated lipid droplets and mitochondria are recognized by alternative ubiquitin-binding SARs. Our analysis identifies proteins that could potentially fulfill this role in yeast. We think that matching of ubiquitin-dependent (but Cue5-independent) autophagic pathways with ubiquitin- and Atg8-binding proteins enlisted here might uncover novel ubiquitin-binding SARs in yeast.Abbreviations: AIM: Atg8-family interacting motif; CUE: coupling of ubiquitin conjugation to ER degradation; ERMES: endoplasmic reticulum-mitochondria encounter structure; HECT: homologous to the E6-AP carboxyl terminus; LD: lipid droplet; SAR: selective autophagy receptor; SGD: Saccharomyces Genome Database; UBA: ubiquitin-associated; UBX: ubiquitin regulatory X; UIM: ubiquitin-interacting motif.

Keywords: Cue5; autophagic receptor; selective autophagy; selective autophagy receptor; ubiquitin-binding protein; ubiquitin-binding receptor

DOI: https://doi.org/10.1080/15548627.2023.2196878

Nat Commun. 2023 Apr 20. 14(1): 2273

Characterization of a fold in TANGO1 evolved from SH3 domains for the export of bulky cargos.

Oliver Arnolds, Raphael Stoll.

Bulky cargos like procollagens, apolipoproteins, and mucins exceed the size of conventional COPII vesicles. During evolution a process emerged in metazoans, predominantly governed by the TANGO1 protein family, that organizes cargo at the exit sites of the endoplasmic reticulum and facilitates export by the formation of tunnel-like connections between the ER and Golgi. Hitherto, cargo-recognition appeared to be mediated by an SH3-like domain. Based on structural and dynamic data as well as interaction studies from NMR spectroscopy and microscale thermophoresis presented here, we show that the luminal cargo-recognition domain of TANGO1 adopts a new functional fold for which we suggest the term MOTH (MIA, Otoraplin, TALI/TANGO1 homology) domain. These MOTH domains, as well as an evolutionary intermediate found in invertebrates, constitute a distinct domain family that emerged from SH3 domains and acquired the ability to bind collagen.

DOI: https://doi.org/10.1038/s41467-023-37705-4

Nat Cancer. 2023 Apr 17.

Impact of context-dependent autophagy states on tumor progression.

Mohamad Assi, Alec C Kimmelman.

Macroautophagy is a cellular quality-control process that degrades proteins, protein aggregates and damaged organelles. Autophagy plays a fundamental role in cancer where, in the presence of stressors (for example, nutrient starvation, hypoxia, mechanical pressure), tumor cells activate it to degrade intracellular substrates and provide energy. Cell-autonomous autophagy in tumor cells and cell-nonautonomous autophagy in the tumor microenvironment and in the host converge on mechanisms that modulate metabolic fitness, DNA integrity and immune escape and, consequently, support tumor growth. In this Review, we will discuss insights into the tumor-modulating roles of autophagy in different contexts and reflect on how future studies using physiological culture systems may help to understand the complexity and open new therapeutic avenues.

DOI: https://doi.org/10.1038/s43018-023-00546-7