Autophagy and beyond:Unraveling the complexity of UNC-51-like kinase 1(ULK1)from biological functions to therapeutic implications

UNC-51-like kinase 1(ULK1),as a serine/threonine kinase,is an autophagic initiator in mammals and a homologous protein of autophagy related protein(Atg)1 in yeast and of UNC-51 in Caenorhabditis elegans.ULK1 is well-known for autophagy activation,which is evolutionarily conserved in protein transport and indispensable to maintain cell homeostasis.As the direct target of energy and nutrition-sensing kinase,ULK1 may contribute to the distribution and utilization of cellular resources in response to metabolism and is closely associated with multiple pathophysiological processes.Moreover,ULK1 has been widely reported to play a crucial role in human diseases,including cancer,neurodegenerative diseases,cardiovascular disease,and infections,and subsequently targeted small-molecule inhibitors or activators are also demonstrated.Interestingly,the non-autophagy function of ULK1 has been emerging,indicating that non-autophagy-relevant ULK1 signaling network is also linked with diseases under some specific contexts.Therefore,in this review,we summarized the structure and functions of ULK1 as an autophagic initiator,with a focus on some new approaches,and further elucidated the key roles of ULK1 in autophagy and non-autophagy.Additionally,we also discussed the relationships between ULK1 and human diseases,as well as illustrated a rapid progress for better understanding of the discovery of more candidate small-molecule drugs targeting ULK1,which will provide a clue on novel ULK1-targeted therapeutics in the future.

Targeting autophagy and beyond:Deconvoluting the complexity of Beclin-1 from biological function to cancer therapy

AbstracBteclin-1 is the firstly-identified mammalian protein of the autophagy machinery,which functions as a molecular scaffold for the assembly of PI3KC3(class II phosphatidylinositol 3 kinase)complex,thus controlling autophagy induction and other cellular trafficking events.Notably,there is mounting evidence establishing the implications of Beclin-1 in diverse tumorigenesis processes,including tumor suppression and progression as well as resistance to cancer therapeutics and CSC(cancer stem-like cell)maintenance.More importantly,Beclin-1 has been confirmed as a potential target for the treatment of multiple cancers.In this review,we provide a comprehensive survey of the structure,functions,and regulations of Beclin-1,and we discuss recent advances in understanding the controversial roles of Beclin-1 in oncology.Moreover,we focus on summarizing the targeted Beclin-1-regulating strategies in cancer therapy,providing novel insights into a promising strategy for regulating Beclin-1 to improvecancer therapeutics in thefuture.