DUBbing Down Translation: The Functional Interaction of Deubiquitinases with the Translational Machinery

Abstract

Cancer cells revamp the regulatory processes that control translation to induce tumor-specific translational programs that can adapt to a hostile microenvironment as well as withstand anticancer therapeutics. Translational initiation has been established as a common downstream effector of numerous deregulated signaling pathways that together culminate in prooncogenic expression. Other mechanisms, including ribosomal stalling and stress granule assembly, also appear to be rewired in the malignant phenotype. Therefore, better understanding of the underlying perturbations driving oncogenic translation in the transformed state will provide innovative therapeutic opportunities. This review highlights deubiquitinating enzymes that are activated/dysregulated in hematologic malignancies, thereby altering the translational output and contributing to tumorigenesis.

Processing of the ribosomal ubiquitin-like fusion protein FUBI-eS30/FAU is required for 40S maturation and depends on USP36

“…Importantly, these observations were confirmed by immunoblotting of the pull-down eluates (Figure 5C), which made USP10 and USP36 prime candidates for ULPs for FUBI-eS30 processing. USP10 is a highly conserved cytoplasmic DUB and has been previously described to interact with 40S subunits (Clague et al, 2019;Kapadia and Gartenhaus, 2019). It is involved in resolution of stalled translation elongation complexes through removal of the regulatory monoubiquitylations from eS10, uS3, and uS5 (Garshott et al, 2020;Jung et al, 2017;Meyer et al, 2020).…”

Processing of the Ribosomal Ubiquitin-Like Fusion Protein FUBI-eS30/FAU is Required for 40S Maturation and Depends on USP36

“…USP10 is a highly conserved cytoplasmic DUB and has been previously described to interact with 40S subunits (Clague et al, 2019; Kapadia and Gartenhaus, 2019). It is involved in resolution of stalled translation elongation complexes through removal of the regulatory monoubiquitylations from eS10, uS3, and uS5 (Garshott et al, 2020; Jung et al, 2017; Meyer et al, 2020).…”

Deubiquitinating enzymes (DUBs): Regulation, homeostasis, and oxidative stress response

“…Another function of DUBs is to regulate the ubiquitin signaling network and thereby control a number of important cellular processes, including protein trafficking, DNA damage repair, and translation regulation ( 74 , 100 , 101 , 102 ). These processes often require rapid and dynamic changes due to shifts in the cellular environment.…”

“…DUBs have also been found to influence translation by regulating ubiquitination of ribosomes themselves ( 102 ). This places DUBs in an important position to regulate global protein synthesis.…”