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In contrast to autophagy induced by nutrient deprivation or pattern recognition receptors, less is known about the effects of cell-mediated immunity on Beclin 1 and ULK1, key regulators of autophagy. Here we studied the molecular mechanisms by which CD40 stimulates autophagy in macrophages. CD40 ligation caused biphasic Jun N-terminal protein kinase (JNK) phosphorylation. The second phase of JNK phosphorylation was dependent on autocrine production of tumor necrosis factor alpha (TNF-\u03b1). TNF-\u03b1 and JNK signaling were required for the CD40-induced increase in autophagy. JNK signaling downstream of CD40 caused Ser-87 phosphorylation of Bcl-2 and dissociation between Bcl-2 and Beclin 1, an event known to stimulate the autophagic function of Beclin 1. However, TNF-\u03b1 alone was unable to stimulate autophagy. CD40 also stimulated autophagy via a pathway that included calcium\/calmodulin-dependent kinase kinase \u03b2 (CaMKK\u03b2), AMP-activated protein kinase (AMPK), and ULK1. CD40 caused AMPK phosphorylation at its activating site, Thr-172. This effect was mediated by CaMKK\u03b2 and was not impaired by neutralization of TNF-\u03b1. CD40 triggered AMPK-dependent Ser-555 phosphorylation of ULK1. CaMKK\u03b2, AMPK, and ULK1 were required for CD40-induced increase in autophagy. CD40-mediated autophagic killing of<jats:named-content content-type=\"genus-species\">Toxoplasma gondii<\/jats:named-content>is known to require TNF-\u03b1. Knockdown of JNK, CaMKK\u03b2, AMPK, or ULK1 prevented<jats:named-content content-type=\"genus-species\">T. gondii<\/jats:named-content>killing in CD40-activated macrophages. The second phase of JNK phosphorylation\u2014Bcl-2 phosphorylation\u2014Bcl-2\u2013Beclin 1 dissociation and AMPK phosphorylation-ULK1 phosphorylation occurred simultaneously at \u223c4 h post-CD40 stimulation. Thus, CaMKK\u03b2 and TNF-\u03b1 are upstream molecules by which CD40 acts on ULK1 and Beclin 1 to stimulate autophagy and killing of<jats:named-content content-type=\"genus-species\">T. gondii<\/jats:named-content>.<\/jats:p>","DOI":"10.1128\/iai.00101-16","type":"journal-article","created":{"date-parts":[[2016,6,29]],"date-time":"2016-06-29T16:26:03Z","timestamp":1467217563000},"page":"2616-2626","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":37,"title":["Identification of Signaling Pathways by Which CD40 Stimulates Autophagy and Antimicrobial Activity against Toxoplasma gondii in Macrophages"],"prefix":"10.1128","volume":"84","author":[{"given":"Elizabeth","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yalitza","family":"Lopez 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