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

Abstract

Ubiquitination functions as a signal to recruit autophagic machinery to damaged organelles and induce their clearance. Here, we report the characterization of FBXO27, a glycoprotein-specific F-box protein that is part of the SCF (SKP1/CUL1/F-box protein) ubiquitin ligase complex, and demonstrate that SCFFBXO27 ubiquitinates glycoproteins in damaged lysosomes to regulate autophagic machinery recruitment. Unlike F-box proteins in other SCF complexes, FBXO27 is subject to N-myristoylation, which localizes it to membranes, allowing it to accumulate rapidly around damaged lysosomes. We also screened for proteins that are ubiquitinated upon lysosomal damage, and identified two SNARE proteins, VAMP3 and VAMP7, and five lysosomal proteins, LAMP1, LAMP2, GNS, PSAP, and TMEM192. Ubiquitination of all glycoproteins identified in this screen increased upon FBXO27 overexpression. We found that the lysosomal protein LAMP2, which is ubiquitinated preferentially on lysosomal damage, enhances autophagic machinery recruitment to damaged lysosomes. Thus, we propose that SCFFBXO27 ubiquitinates glycoproteins exposed upon lysosomal damage to induce lysophagy.

Key Role of Microtubule and Its Acetylation in a Zinc Oxide Nanoparticle–Mediated Lysosome–Autophagy System

“…Ubiquitination (Ub) is an important component of the intracellular degradation process and is also involved in mitophagy and lysophagy . In our study, Ub increased in a time‐dependent manner, whereas Zn 2+ sequestration significantly reduced Ub (Figure C).…”

“…For example, autophagosomes engulf impaired mitochondria and then degrade them for mitochondrial renewal . A new autophagy process related to impaired lysosome renewal, termed lysophagy, in which impaired lysosomes are sequestered via autophagy, allowing a number of normal lysosomes to be maintained, was also recently reported …”

“…For example, emerging evidence suggests that impaired lysosomes are selectively sequestered by autophagosomes, termed lysophagy, which is helpful for lysosome homeostasis. The luminal proteins of lysosomes exposed to the cytosol following membrane rupture probably are the key factor for lysophagy initiation . However, whether lysophagy is involved in NM‐induced autophagy has not been studied.…”

Triggered recruitment of ESCRT machinery promotes endolysosomal repair

“…Lysophagy is promoted by recruitment of cytoplasmic proteins including galectins and glycoprotein-specific ubiquitin ligases to abnormally exposed lumenal glycans on the afflicted compartment (1–6). Whether damaged endolysosomes can avoid autophagic degradation and instead be fully repaired is less clear but has been suspected (7–11).…”

F‐box/WD Repeat‐Containing Protein 5 Mediates the Ubiquitination of Apoptosis Signal‐Regulating Kinase 1 and Exacerbates Nonalcoholic Steatohepatitis in Mice

“…The substrate specificity of SCF E3 ligases is determined largely by the F‐box protein . The function of SCF ligases has been reported in multiple pathophysiological processes, especially in metabolic homeostasis . For instance, the SCF FBXW7 complex plays key roles in regulating liver lipogenesis .…”