Reference: Simões V, et al. (2022) Redox-sensitive E2 Rad6 controls cellular response to oxidative stress via K63-linked ubiquitination of ribosomes. Cell Rep 39(8)

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Abstract


Protein ubiquitination is an essential process that rapidly regulates protein synthesis, function, and fate in dynamic environments. Within its non-proteolytic functions, we showed that K63-linked polyubiquitinated conjugates heavily accumulate in yeast cells exposed to oxidative stress, stalling ribosomes at elongation. K63-ubiquitinated conjugates accumulate mostly because of redox inhibition of the deubiquitinating enzyme Ubp2; however, the role and regulation of ubiquitin-conjugating enzymes (E2) in this pathway remained unclear. Here, we show that the E2 Rad6 associates and modifies ribosomes during stress. We further demonstrate that Rad6 and its human homolog UBE2A are redox regulated by forming a reversible disulfide with the E1 ubiquitin-activating enzyme (Uba1). This redox regulation is part of a negative feedback regulation, which controls the levels of K63 ubiquitination under stress. Finally, we show that Rad6 activity is necessary to regulate translation, antioxidant defense, and adaptation to stress, thus providing an additional physiological role for this multifunctional enzyme.

Reference Type
Journal Article | Research Support, N.I.H., Extramural | Research Support, N.I.H., Intramural | Research Support, Non-U.S. Gov't | Research Support, U.S. Gov't, Non-P.H.S.
Authors
Simões V, Cizubu BK, Harley L, Zhou Y, Pajak J, Snyder NA, Bouvette J, Borgnia MJ, Arya G, Bartesaghi A, ... Show all
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