ZAKα Recognizes Stalled Ribosomes through Partially Redundant Sensor Domains

Abstract

Highlights d ZAKa binds directly to the ribosome and is the proximal sensor of ribotoxic stress d ZAKa contains two partially redundant domains for sensing ribotoxic stress d Constitutive activation of ZAKa is associated with developmental defects in humans d Deficiency in the ribotoxic stress response compromises lifespan in C. elegans

Ribosomal stress-surveillance: three pathways is a magic number

“…An activating role for ZAK also in ribotoxin-induced RSR was demonstrated in 2008 by Jandhyala et al. They showed that both chemical inhibition and siRNA-mediated knockdown of ZAK prevented MAP kinase activation in response to ricin and Stx ( 71 ), which was later corroborated in ZAK knockout cells ( 72 ). Later, the same group showed that bone-marrow derived macrophages established from zak -/- mice were completely deficient for p38 and JNK activation upon ricin exposure ( 77 ).…”

“…Originally, overexpression of these proteins were found to promote apoptosis in a hepatoma cell line ( 74 ), and ZAK was also reported to be activated by osmotic stress, causing disruption of actin fibers and altered cell morphology ( 75 ). Since then multiple functions of ZAK have been proposed, including the activation p38 and JNK in response to ribotoxic stress ( 61 , 70 , 72 , 76 ). This was first described in 2005 by Wang et al.…”

“…Additionally, toxins that inactivate the elongation factor EEF2 do not initiate RSR ( 47 , 78 ). A recent study by our group showed that the long isoform of ZAK, ZAKα, constitutes a molecular sensor of ribotoxic stress by virtue of two C-terminal ribosome binding domains ( 72 ) (Figure 2D ). The shorter ZAKβ isoform does not contain such domains and does not support RSR signaling.…”

Activation of the antiviral factor RNase L triggers translation of non-coding mRNA sequences

“…This highlights a potential role of ribosome rescue factors during RNase L activation in maintaining a pool of free ribosomes. Prolonged activation of RNase L could overwhelm the ribosome rescue system and lead to ribosome queues that are, in turn, recognized by sensors of ribosome stalling, such as ZAKα, that could trigger apoptosis mediated by JNK (Vind et al, 2020;Wu et al, 2020a). Such a model could account for the observation that JNK is critical to RNase-L mediated apoptosis (Li et al, 2004), a process thought to be beneficial for eliminating cells infected by viruses.…”

Mosaic changes to the global transcriptome in response to inhibiting ribosome formation versus inhibition of ribosome function

“…One such regulatory process originates from ribosomal collisions on the mRNA that activate the kinase Gcn2 to phosphorylate eIF2a triggering inhibition of translation initiation (Wu et al 2019;Juszkiewicz et al 2020;Wu et al 2020) and favors the expression of a subset of genes through ribosome interaction with upstream open reading frames (Hinnebusch et al 2016;Pakos-Zebrucka et al 2016). During extreme stress, another kinase, ZAKa, phosphorylates map kinases resulting in apoptosis and cell death (Vind et al 2020;Wu et al 2020). Another pathway limiting expression of rprotein genes is actuated by obstruction of ribosome assembly, which causes accumulation of insoluble aggregates of ribosomal and other proteins including Ifh1 (Albert et al 2019a).…”