Tissue-specific safety mechanism results in opposite protein aggregation patterns during aging

Abstract

During aging, proteostasis capacity declines and aggregation-prone proteins become instable, accumulating in protein aggregates both inside and outside cells. Both in disease and during aging, proteins selectively aggregate in certain tissues and not others. Yet, tissue-specific regulation of protein aggregation remains poorly understood. Surprisingly, we found that the inhibition of three core protein quality control systems, i.e. chaperones, proteasome and macroautophagy, leads to lower levels of age-dependent protein aggregation in C. elegans pharyngeal muscles, but higher levels in body-wall muscles. We describe a novel safety mechanism called SAPA that selectively targets newly synthesized aggregation-prone proteins to suppress aggregation and proteotoxicity. vha-12 and scav-3 mutants reveal that SAPA relies on macroautophagy-independent lysosomal degradation. Furthermore, SAPA involves several previously uncharacterized components of the intracellular pathogen response. We propose that SAPA represents an anti-aggregation machinery targeting aggregation-prone proteins for lysosomal degradation.

Targeted protein degradation: from small molecules to complex organelles—a Keystone Symposia report

“…If the protein quality control system is also impaired, aggregation accelerates in tissues like the body muscles. However, in the pharyngeal muscles, a safety mechanism is triggered in which unstable aggregation‐prone proteins are directly targeted to the lysosome 64,65 …”

“…However, in the pharyngeal muscles, a safety mechanism is triggered in which unstable aggregationprone proteins are directly targeted to the lysosome. 64,65 David also described work on understanding the mechanisms for extracellular proteostasis. Extracellular proteins are subject to damage via oxidation and mechanical stress; however, little is known about the extracellular protein quality control components, partly because of a lack of good models available for extensive genetic screens in which to evaluate it.…”

“…David showed that defects in the protein quality control system trigger a safety mechanism in the pharynx that prevents accumulation of newly synthesized aggregation-prone proteins by targeting them for degradation via the lysosome. 64,65 RNA-seq analysis identified several genes that may be participating in this safety mechanism, including genes involved in the response to intracellular pathogens. 66 David put forth a model wherein the proteome naturally becomes unstable and aggregates as part of normal aging.…”

“…While protein aggregation increased in the body wall muscle, it decreased in the pharyngeal muscles. David showed that defects in the protein quality control system trigger a safety mechanism in the pharynx that prevents accumulation of newly synthesized aggregation‐prone proteins by targeting them for degradation via the lysosome 64,65 …”

Impairment of lipid homoeostasis causes accumulation of protein aggregates in the lysosome

“…In contrast, knocking down many chaperones, including HSPA4, HSP90AB1, DNAJB6, and several subunits of TRiC chaperonins, paradoxically reduces the ProteoStat signal. Perturbing chaperones can trigger the newly described safeguard against protein aggregation mechanism that targets certain newly synthesized aggregation-prone proteins to the lysosome, notably before large visible aggregates are formed 18 . Alternatively, the paradoxical effect of chaperone inhibition on ProteoStat signal could be due to upregulation of heat shock response as a negative feedback following the initial HSP70 or HSP90 inhibition 19–21 .…”