Ubiquitin-mediated degradation at the Golgi apparatus

Abstract

The Golgi apparatus is an essential organelle of the secretory pathway in eukaryotic cells. It processes secretory and transmembrane proteins and orchestrates their transport to other endomembrane compartments or the plasma membrane. The Golgi apparatus thereby shapes the cell surface, controlling cell polarity, cell-cell communication, and immune signaling. The cytosolic face of the Golgi hosts and regulates signaling cascades, impacting most notably the DNA damage response and mitosis. These essential functions strongly depend on Golgi protein homeostasis and Golgi integrity. Golgi fragmentation and consequent malfunction is associated with neurodegenerative diseases and certain cancer types. Recent studies provide first insight into the critical role of ubiquitin signaling in maintaining Golgi integrity and in Golgi protein quality control. Similar to well described pathways at the endoplasmic reticulum, ubiquitin-dependent degradation of non-native proteins prevents the accumulation of toxic protein aggregates at the Golgi. Moreover, ubiquitination regulates Golgi structural rearrangements in response to cellular stress. Advances in elucidating ubiquitination and degradation events at the Golgi are starting to paint a picture of the molecular machinery underlying Golgi (protein) homeostasis.

The Dsc ubiquitin ligase complex identifies transmembrane degrons to degrade orphaned proteins at the Golgi

“… (A-D) Volcano plots showing the H/L peptide ratios of proteins from heavy 13 C 6 , 15 N 2 -L-lysine labeled WT cells against light 12 C 6 , 14 N 2 -L-lysine L-lysine labeled tul1Δ (A, B) or vps4Δ (A, D) mutants. Total proteome of (A) WT / tul1Δ mutants or (C) WT / vps4Δ mutants, transmembrane proteins (TMPs) in red; (B, D) only transmembrane proteome.…”

“…Cells were pre-cultured for 24 hours in 10 mL medium at 26 °C. WT cells were grown with “heavy” [ 13 C 6 15 N 2 ]-L-lysine (Sigma) at a final concentration of 20 mg/L and the tul1Δ and vps4Δ mutant cells were grown with “light” [ 12 C 6 14 N 2 ]-L-lysine at a final concentration of 20 mg/L. Cells were grown to mid-log phase (OD600 ≤ 0.8) for 12 generations (24hours).…”

“…Despite the pivotal role of the Golgi in protein sorting, and in cellular - and organismal health, Golgi-based protein quality control (PQC) processes have remained largely unknown. While there is emerging evidence that PQC systems operate at the Golgi 4-7 to detect and degrade misfolded and orphaned proteins (proteins that mislocalize or fail to assemble with their protein binding partners 8,9 ), the underlying molecular mechanisms are not well characterized 10-12 .…”

Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy

“…The Golgi Complex (GC) is an example, as functional and structural alterations of the GC [ 128 , 129 , 130 ] and the dysregulation of GC-centered signaling cascades [ 131 ] have been observed in cancer. There is evidence that a small number of E3s localize to the GC, where they mediate the ubiquitination of resident proteins, thereby regulating organelle structural integrity and vesicle trafficking [ 132 ]. For example, the CUL7 FBXW8 complex regulates the turnover of GRASP65.…”