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Autophagy plays essential roles in diverse biological events, range from cellular homeostasis and proliferation to aging, immune response, and contributes to various disorders if it go awry. Because of the paramount importance of autophagy, it is therefore of vital significance that any autophagy is carefully balanced. Autophagy involves the sequestration of cytoplasmic cargo inside double-membrane vesicles (autophagosomes) and fused with lysosome (autolysosome), where the captured material is degraded. The initiation and formation of autophagosomes involves multiple steps through multiple protein complexes. Beclin 1 is a key regulatory protein in Phosphoinositide 3-kinase (PI3K) complex during the early steps. The initiation of phagophore formation is regulated by a protein complex comprising Vps15, Vps34, Beclin 1, and other regulatory proteins, such as Bcl-2 and Rubicon. Recent studies have shown the important role of Beclin 1 in Toll-like receptor (TLR) 4-mediated autophagy. Here we demonstrated that Triad3A, an E3 ubiquitin protein ligase, specifically interacted with Beclin 1 but not with other adapter proteins in PI3K complex in the murine macrophage cell line RAW264.7 and in bone marrow-derived macrophages (BMDM) stimulated with lipopolysaccharide (LPS). We further showed that Triad3A accelerated Beclin 1 degradation through ubiquitination, thus inhibition of autophagy. In addition, S. typhimurium infection-induced autophagy was enhanced if Triad3A was knockdown using specific siRNA in BMDM, and contributed to the restriction of bacteria growth. This further suggested a role of the Triad3A in controlling autophagy in response to microbial infections. Taken together, our study have unveiled a new mechanism of the regulation of autophagy through ubiquitination of Beclin 1 by Triad3A, which represent a novel pathway of innate immunity link to autophagy. Triad3A-meidiated regulation might provide a novel therapeutic approach for controlling infectious diseases.