As organisms age, they often accumulate protein aggregates that are thought to be 55 toxic, potentially leading to age-related diseases. This accumulation of protein 56 aggregates is partially attributed to a failure to maintain protein homeostasis. A variety of 57 genetic factors have been linked to longevity, but how these factors also contribute to 58 protein homeostasis is not completely understood. In order to understand the 59 relationship between aging and protein aggregation, we tested how a gene that 60 regulates lifespan and age-dependent locomotor behaviors, p38 MAPK (p38Kb), 61 influences protein homeostasis as an organism ages. We find that p38Kb regulates age-62 dependent protein aggregation through an interaction with the Chaperone-Assisted 63 Selective Autophagy complex. Furthermore, we have identified Lamin as an age-64 dependent target of p38Kb and the Chaperone-Assisted Selective Autophagy complex. 65 66 Introduction 67 68 Protein turnover is critical for maintaining tissue health as many proteins become 69 damaged or misfolded during normal tissue functions. Therefore, the cell utilizes a 70 variety of protein quality control mechanisms to refold or degrade these damaged 71 proteins, including the ubiquitin proteasome system and macroautophagy. During aging, 72 protein quality control mechanisms become less efficient leading to the accumulation of 73 damaged or misfolded proteins that begin to form protein aggregates 1 . It has been 74 hypothesized that these aggregates are toxic and may lead to the deleterious 75 phenotypes associated with normal aging, such as impaired tissue function 1 . 76Furthermore, decreased protein aggregation has been associated with longevity. For 77 example, over-expression of Foxo leads to an increased lifespan but also a concordant 78 4 decrease in protein aggregation in C. elegans, Drosophila, and mice 2-6 , suggesting that 79 lifespan and protein aggregation are tightly linked processes. However, the molecular 80 mechanisms that underlie the relationship between aging and protein homeostasis have 81 not been fully characterized. 82
83One pathway that has been linked to both aging and protein homeostasis is the 84 stress response p38 MAPK (p38K) pathway. In mammals, there are four p38K genes (α, 85 β, γ, and δ), and p38Kα has been linked to both the inhibition 7,8 and induction 9,10 of 86 macroautophagy, in particular in response to oxidative stress 11,12 . In addition, p38Kα 87 has been linked to regulating macroautophagy in cellular senescence [13][14][15] . However, 88 how p38K signaling may contribute to protein homeostasis in response to natural aging 89is not well understood. The fruit fly Drosophila melanogaster has two canonical p38K 90 genes (p38Ka and p38Kb), and we have previously reported that p38Kb acts in the adult 91 musculature to regulate aging. We found that over-expression of p38Kb leads to 92 increased lifespan while loss of p38Kb results in a short lifespan and age-dependent 93 locomotor behavior defects 16 . In addition, oxidatively damaged ...
