Ubiquitination and selective autophagy

Abstract

Ubiquitination has long been recognised as a key determinator of protein fate by tagging proteins for proteasomal degradation. Most recently, the ability of conjugated ubiquitin chains to confer selectivity to autophagy was demonstrated. Although autophagy was first believed to be a bulk, non-selective 'self-eating' degradative process, the molecular mechanisms of selectivity are now starting to emerge. With the discovery of autophagy receptors -which bind both ubiquitinated substrates and autophagy specific light chain 3 (LC3) modifier on the inner sheath of autophagosomes -a new pathway of selective autophagy is being unravelled. In this review, we focus on the special role of ubiquitin signals and selective autophagy receptors in sorting a variety of autophagic cargos. FactsThe ubiquitin-proteasomal system (UPS) and the ubiquitinlike system (UBL) have functional similarity. Ubiquitination is frequently a prerequisite for substrate recognition and determines selectivity in autophagy in higher eukaryotes. Crosstalk between ubiquitination and autophagy is provided by autophagic adaptor proteins (or autophagy receptors), which bind both ubiquitin and autophagyspecific UBL modifiers (LC3 (light chain 3)/GABARAP (gamma-aminobutyric acid receptor-associated protein)). To date, seven autophagy receptors have been identified, which specifically regulate the selective autophagosomal degradation of large protein aggregates, mitochondria and bacterial pathogens. Open QuestionsWhat are the spatio-temporal mechanisms governing the dynamics of selective autophagosomal degradation? Are there regulatory feedback loops, whereby autophagy activity affects ubiquitination?What are the molecular basics that regulate selective autophagy under certain conditions? Are there germline or somatic mutations in key autophagy regulators that are causative for disease? What is the interplay between selective autophagy pathways and macroautophagy during starvation?Ubiquitin, a small protein consisting of 76 amino acids, is found in all tissues of eukaryotic organisms. With only three aminoacid differences between mammals, yeast and plants, ubiquitin displays a remarkable evolutionary conservation.

The ubiquitin system: a critical regulator of innate immunity and pathogen–host interactions

“…63 Ubiquitin appears to represent a common 'eat-me' signal in various selective autophagic pathways including xenophagy. 64 For example, both K48-and K63-linked ubiquitin chains were previously observed to accumulate around the vacuolar pathogen Mtb during infection in macrophages. Recent research partially sheds light on the underlying mechanism: the bacterial ESX-1 T7SS-mediated phagosomal permeabilization allows the cGAS-STING-dependent cytosolic DNA sensor pathway to access extracellular bacterial DNA and then triggers parkinmediated K63-linked ubiquitination surrounding the Mtbcontaining phagosome, which is required for the delivery of bacilli to autophagosomes.…”

Autophagy regulates T lymphocyte proliferation through selective degradation of the cell-cycle inhibitor CDKN1B/p27Kip1

“…Several autophagy receptor proteins facilitate the loading of targets into phagophores. 42 The receptor molecule SQSTM1 is one of these autophagy receptors. SQSTM1 can associate with LC3 during the induction of autophagy and at the same time binds ubiquitinated proteins.…”

Ubiquitination of exposed glycoproteins by SCF FBXO27 directs damaged lysosomes for autophagy

“…In these systems, ubiquitination often plays a pivotal role in directing the autophagic machinery to substrates (12). It has been shown that ubiquitin-positive inclusion bodies are degraded by autophagy via p62, an adaptor protein linking ubiquitin to LC3, an autophagosome marker (13).…”