Lining up for quality control: linear ubiquitin and proteotoxicity

Abstract

The post‐translational modification of proteins with linear ubiquitin (Ub) has previously been shown to be important for regulating inflammatory and immunological signaling in response to cellular pathogens. However, other functions of linear Ub are currently poorly defined. In this issue of The EMBO Journal, van Well and colleagues define a new role for linear Ub in regulating the intracellular stability and proteotoxicity of protein aggregates implicated in neurodegenerative diseases. This work provides new insights into the pathologic and potential therapeutic implications for linear Ub in the pathogenesis of these disorders.

Figure 1. LUBAC‐dependent regulation of Htt aggregates

Illustration showing the molecular mechanisms involved in recruiting LUBAC to Htt aggregates and the functional implications of this activity on cellular function. LUBAC is recruited to Htt aggregates through a mechanism involving the AAA⁺ ATPase p97. Once localized, LUBAC poly‐ubiquitinates Htt aggregates to influence multiple aspects of aggregate biology. 1) LUBAC‐dependent poly‐ubiquitination reduces aggregate levels through a process likely involving increased targeting of Htt subunits to the proteasome. 2) Linear Ub chains on Htt aggregates can recruit proteins such as NEMO that bind to linear M1 Ub linkages to remodel the aggregate surface and potentially induce localized signaling. 3) LUBAC‐dependent ubiquitination shields aggregates to prevent aberrant interactions with low complexity transcription factors such as SP1. Blocking SP1 interactions with aggregates increases SP1 transcriptional activity, which includes the regulation of LUBAC subunits such as HOIP and SHARPIN. 4) LUBAC‐dependent linear ubiquitination of Htt aggregates suppresses phosphorylation of c‐Jun, reflecting reduced signaling through the JNK/c‐Jun signaling pathway.