Abstract
During autophagy, actin filament networks move and remodel cellular membranes to form autophagosomes that enclose and metabolize cytoplasmic contents. Two actin regulators, WHAMM and JMY, participate in autophagosome formation, but the signals linking autophagy to actin assembly are poorly understood. We show that, in nonstarved cells, cytoplasmic JMY colocalizes with STRAP, a regulator of JMY's nuclear functions, on nonmotile vesicles with no associated actin networks. Upon starvation, JMY shifts to motile, LC3-containing membranes that move on actin comet tails. LC3 enhances JMY's de novo actin nucleation activity via a cryptic actin-binding sequence near JMY's N terminus, and STRAP inhibits JMY's ability to nucleate actin and activate the Arp2/3 complex. Cytoplasmic STRAP negatively regulates autophagy. Finally, we use purified proteins to reconstitute LC3- and JMY-dependent actin network formation on membranes and inhibition of network formation by STRAP. We conclude that LC3 and STRAP regulate JMY's actin assembly activities in trans during autophagy.
Highlights
Autophagy is a catabolic process during which membranes move and remodel to form autophagosomes, organelles bounded by double membranes that engulf and metabolize cytoplasmic contents (Shibutani and Yoshimori, 2014)
Two groups identified a pair of related nucleation-promoting factors, WASP homologue associated with membranes and microtubules (WHAMM) and junction mediating and regulatory protein (JMY), as contributors to autophagosome biogenesis
Addition of soluble STRAP to this reaction does not prevent recruitment of JMY to the LC3-coated microspheres, but strongly suppresses formation of a branched actin network (Fig. 8 D), consistent with STRAP’s ability to inhibit JMY’s actin-nucleating activity and with an inhibitory role for STRAP in JMY-mediated autophagosome movement. It promotes actin filament assembly by multiple mechanisms (Zuchero et al, 2009), JMY was first described as a coactivator of p53-mediated apoptosis that accumulates in the nucleus in response to DNA damage
Summary
Autophagy is a catabolic process during which membranes move and remodel to form autophagosomes, organelles bounded by double membranes that engulf and metabolize cytoplasmic contents (Shibutani and Yoshimori, 2014). In 2015, Mi et al (2015) found evidence that branched actin networks created by the Arp2/3 complex drive some of the membrane movements required for autophagosome formation. After this initial discovery, two groups identified a pair of related nucleation-promoting factors, WASP homologue associated with membranes and microtubules (WHAMM) and junction mediating and regulatory protein (JMY), as contributors to autophagosome biogenesis. Coutts and La Thangue (2015) found that JMY promotes autophagy by directing actin assembly on membranes that contain the autophagy regulator, LC3 They noticed that the N-terminal region of JMY contains a consensus LC3-interacting region (LIR) found in many autophagy-related proteins. Little is known about how upstream factors regulate WHAMM- or JMY-directed actin assembly, but the results of Coutts and Lathangue (2015) suggest that JMY’s N-terminal region might regulate both localization and nucleation activity
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