# Discovery of Golgi membrane-associated degradation (GOMED) pathway: a focus on 15 years of ultrastructural analyses

## TL;DR

This paper reviews the GOMED pathway, a Golgi-based degradation system that helps cells remove damaged components and is linked to diseases like neurodegeneration and cancer.

## Contribution

The paper provides a detailed ultrastructural and mechanistic overview of GOMED, emphasizing its distinct role in cellular degradation and its physiological and pathological significance.

## Key findings

- GOMED is an Atg5/Atg7-independent pathway that differs from canonical autophagy in membrane origin and substrate specificity.
- Wipi3 is essential for GOMED, and its dysfunction causes cerebellar degeneration in mice.
- GOMED contributes to mitochondrial clearance during erythroid differentiation and neuronal homeostasis.

## Abstract

In this review, we focus on the ultrastructural characteristics of the Golgi membrane-associated degradation (GOMED) pathway, which have been clarified by electron microscopy, and highlight recent advances in the elucidation of its molecular mechanism and physiological roles. The discovery of GOMED, an Atg5/Atg7-independent degradation pathway that differs from canonical autophagy in membrane origin, stimuli and substrate specificity, has substantially expanded our understanding of intracellular degradation systems. In 2009, we identified GOMED as a novel, evolutionarily conserved autophagic pathway and demonstrated its role in intracellular degradation across eukaryotes, from yeast to mammals. We identified the conserved protein Hsv2/Wipi3 as an essential GOMED protein, which translocates to the trans-Golgi upon induction and remodels Golgi membranes into cup-shaped structures that engulf cytoplasmic components for lysosomal degradation. These processes contribute to organelle and secretory granule turnover, as well as mitochondrial clearance during erythroid differentiation. Moreover, neuronal-specific ablation of Wipi3 in mice causes severe cerebellar degeneration, implicating GOMED in tissue development and homeostasis. As these mechanisms are associated with diseases, such as neurodegenerative disorders and cancer, GOMED mechanisms should also be considered when establishing therapeutic strategies for these diseases.

Morphological and Mechanistic Insights into GOMED: A Golgi-Membrane Degradation Pathway I. GOMED Stimulation Golgi membrane-associated degradation (GOMED) is induced by various cellular stresses, such as DNA damage and the inhibition of cargo transport within the Golgi owing to an overloaded transport pathway. Under such stressed conditions, GOMED degrades proteins that accumulate and stagnate in the Golgi. Chemical agents such as the DNA-damaging drug etoposide and 1,3-cyclohexanebis - a compound that interferes with coatomer binding to Golgi membranes, thereby inhibiting anterograde trafficking - can also induce GOMED[11,12]. Key regulatory steps involve Ulk1 phosphorylation dynamics; see details in refs. 23, 50, and 51. II. Golgi Transformation Upon GOMED induction, the Golgi undergoes morphological reorganization. In animal cells, the normally contiguous Golgi stacks fragment into dispersed ministacks, concomitant with reduced phosphatidylinositol 4-phosphate [PI(4)P] levels on Golgi membranes[12]. III. Isolation Membrane Formation The trans-Golgi of the ministack Golgi separates from the stack structure, forming an isolation membrane. At this stage, dephosphorylated Wipi3 translocates from the cytoplasm to the Golgi[42]. The isolation membrane subsequently engulfs mitochondria, secretory granules, and other substrates. However, the tethering molecules and adaptors involved in this process remain unidentified. IV. Autophagosome Formation The isolation membrane encloses the substrates, forming a double-membrane autophagosome. This process requires Dram and Rab9[11,49]. V. Autolysosome Formation The double-membraned autophagosome fuses with lysosomes to form single-membraned autolysosomes, where the enclosed contents are degraded. Further fusion between autolysosomes, as well as between autolysosomes and endosomes, contribute to autolysosome enlargement.

Morphological and Mechanistic Insights into GOMED: A Golgi-Membrane Degradation Pathway I. GOMED Stimulation Golgi membrane-associated degradation (GOMED) is induced by various cellular stresses, such as DNA damage and the inhibition of cargo transport within the Golgi owing to an overloaded transport pathway. Under such stressed conditions, GOMED degrades proteins that accumulate and stagnate in the Golgi. Chemical agents such as the DNA-damaging drug etoposide and 1,3-cyclohexanebis - a compound that interferes with coatomer binding to Golgi membranes, thereby inhibiting anterograde trafficking - can also induce GOMED[11,12]. Key regulatory steps involve Ulk1 phosphorylation dynamics; see details in refs. 23, 50, and 51. II. Golgi Transformation Upon GOMED induction, the Golgi undergoes morphological reorganization. In animal cells, the normally contiguous Golgi stacks fragment into dispersed ministacks, concomitant with reduced phosphatidylinositol 4-phosphate [PI(4)P] levels on Golgi membranes[12]. III. Isolation Membrane Formation The trans-Golgi of the ministack Golgi separates from the stack structure, forming an isolation membrane. At this stage, dephosphorylated Wipi3 translocates from the cytoplasm to the Golgi[42]. The isolation membrane subsequently engulfs mitochondria, secretory granules, and other substrates. However, the tethering molecules and adaptors involved in this process remain unidentified. IV. Autophagosome Formation The isolation membrane encloses the substrates, forming a double-membrane autophagosome. This process requires Dram and Rab9[11,49]. V. Autolysosome Formation The double-membraned autophagosome fuses with lysosomes to form single-membraned autolysosomes, where the enclosed contents are degraded. Further fusion between autolysosomes, as well as between autolysosomes and endosomes, contribute to autolysosome enlargement.

This review highlights the ultrastructural characteristics and molecular mechanism of GOMED, an evolutionarily conserved autophagic pathway. Via reorganizing Golgi membranes, GOMED eliminates mitochondria during erythroid differentiation, and maintains neuronal homeostasis. Golgi-translocating protein Wipi3 is essential for GOMED, with its dysfunction linked to cerebellar degeneration, emphasizing GOMED’s role in physiological functions.