Polyubiquitin Chains Linked by Lysine Residue 48 (K48) Selectively Target Oxidized Proteins In Vivo.
Aims: Ubiquitin is a highly conserved protein modifier that heavily accumulates during the oxidative stress response. Here, we investigated the role of the ubiquitination system, particularly at the linkage level, in the degradation of oxidized proteins. The function of ubiquitin in the removal of oxidized proteins remains elusive because of the wide range of potential targets and different roles that polyubiquitin chains play. Therefore, we describe in detail the dynamics of the K48 ubiquitin response as the canonical signal for protein degradation. We identified ubiquitin targets and defined the relationship between protein ubiquitination and oxidation during the stress response. Results: Combining oxidized protein isolation, linkage-specific ubiquitination screens, and quantitative proteomics, we found that K48 ubiquitin accumulated at both the early and late phases of the stress response. We further showed that a fraction of oxidized proteins are conjugated with K48 ubiquitin. We identified ∼750 ubiquitinated proteins and ∼400 oxidized proteins that were modified during oxidative stress, and around half of which contain both modifications. These proteins were highly abundant and function in translation and energy metabolism. Innovation and Conclusion: Our work showed for the first time that K48 ubiquitin modifies a large fraction of oxidized proteins, demonstrating that oxidized proteins can be targeted by the ubiquitin/proteasome system. We suggest that oxidized proteins that rapidly accumulate during stress are subsequently ubiquitinated and degraded during the late phase of the response. This delay between oxidation and ubiquitination may be necessary for reprogramming protein dynamics, restoring proteostasis, and resuming cell growth.
Manohar, S; Jacob, S; Wang, J; Wiechecki, KA; Koh, HWL; Simões, V; Choi, H; Vogel, C; Silva, GM
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