Suppression of autophagic activity by Rubicon is a signature of aging

Abstract

Autophagy, an evolutionarily conserved cytoplasmic degradation system, has been implicated as a convergent mechanism in various longevity pathways. Autophagic activity decreases with age in several organisms, but the underlying mechanism is unclear. Here, we show that the expression of Rubicon, a negative regulator of autophagy, increases in aged worm, fly and mouse tissues at transcript and/or protein levels, suggesting that an age-dependent increase in Rubicon impairs autophagy over time, and thereby curtails animal healthspan. Consistent with this idea, knockdown of Rubicon extends worm and fly lifespan and ameliorates several age-associated phenotypes. Tissue-specific experiments reveal that Rubicon knockdown in neurons has the greatest effect on lifespan. Rubicon knockout mice exhibits reductions in interstitial fibrosis in kidney and reduced α-synuclein accumulation in the brain. Rubicon is suppressed in several long-lived worms and calorie restricted mice. Taken together, our results suggest that suppression of autophagic activity by Rubicon is one of signatures of aging.

Structural basis for autophagy inhibition by the human Rubicon-Rab7 complex

“…Rubicon, along with Bcl-2 15 , is one of most prominent negative regulators of autophagy and is therefore considered a promising target for autophagy inducing therapeutics 11,12 . Despite its significance, however, the only available structural data have been a 6 Å cryo-EM and hydrogen-deuterium exchange characterization of a short portion of the central IDR as bound to PI3KC3-C2 8 .…”

“…Rubicon is targeted to its sites of action by the late endosomal small GTPase Rab7 9,10 . Autophagy suppression by Rubicon in aging has been linked to decreased clearance of α-synuclein aggregates in neural tissues, impairment of liver cell homeostasis, and interstitial fibrosis in the kidney [11][12][13] . Together with another target for autophagy inducing therapeutics, Bcl-2 14,15 , Rubicon is one of very few known broadly-acting negative regulators of autophagy.…”

The Aging Heart: Mitophagy at the Center of Rejuvenation

“…Current efforts are dedicated to understanding the biological process of aging and to identify pathways that can be targeted to extend health and life spans. Interestingly, it has been demonstrated that many of the pathways that improve health and extend longevity in various organisms all converge on autophagy (1)(2)(3)(4)(5)(6)(7)(8). Autophagy is a catabolic pathway that is responsible for recycling cellular proteins and organelles to maintain energy homeostasis.…”

“…It is also a key pathway in cellular quality control by eliminating dysfunctional or unwanted organelles and protein aggregates. However, there is strong evidence that autophagy is decreased with age in tissues, including the heart (5,(9)(10)(11)(12)(13)(14)(15).…”

Computational design of anti-CRISPR proteins with improved inhibition potency and expanded specificity

“…The recent discovery of phage-derived anti-CRISPR proteins 4-6 , i.e. potent inhibitors of Cas effectors, provides a shut-off mechanism that can keep this powerful technology in check 7 and enhance the precision at which genome perturbations can be made [8][9][10][11] . While mining of sequence databases and screening of phage libraries proved to be powerful strategies to discover Acrs targeting a variety of Cas effectors 5, 6, 12-18 , these approaches are inherently limited to the naturally occurring protein sequence space.…”