The ability to degrade intracellular proteins in a controlled manner is an important cellular function. It is utilized to remove and recycle unnecessary, damaged and/or harmful components, which is an essential ability to maintain cellular homeostasis and health. The most well-known routes to selective degradation of proteins are proteasomal degradation and selective autophagy. In both pathways, proteins targeted for degradation are marked polyubiquitination (polyUb), with chains that are linked at lysine K48 and K63, respectively.

A less well-characterized pathway for protein degradation is Golgi membrane-associated degradation (GOMED). GOMED mainly degrades proteins that pass through the Golgi apparatus on route to the plasma membrane or destined for secretion. Like in autophagy, the substrate destined for degradation is engulfed in a double membrane, which later fuses with a lysosome. However, in GOMED the membrane originates for the trans-Golgi network (TGN) rather than from the endoplasmic reticulum (ER). The molecular players also differ, with GOMED being dependent on Wipi3/4 an Rab9, which are indispensable for traditional autophagy.

A recent study published in Nature communications just added another piece to the molecular players involved in GOMED (Nibe-Shirakihara,2025). Optineurin (OPTN), is an ubiquitin-binding adaptor protein involved in several cellular processes. In the subcellular resource of the HPA, optineurin localizes to the cytoplasm in a punctate pattern, which is concentrated in the perinuclear region, where also the Golgi apparatus resides. The study by Nibe-Shirakihara et al. revealed that optineurin is required for protein degradation by GOMED specifically through recognition of K33-polyUb. Indeed, induction of GOMED further enhances its localization to the TGN and eventually to autolysosomes. Interestingly, the OPTN gene is associated with Amyotrophic lateral sclerosis (ALS) and glaucoma (Guo,2020), and some of the mutations seen in people with ALS are indeed located in the domain shown to be involved in K33-polyUb recognition (Nibe-Shirakihara,2025, Del Bo,2011, Feng,2019), suggesting a possible role for GOMED in the disease.