ULK1/2 Restricts the Formation of Inducible SINT-Speckles, Membraneless Organelles Controlling the Threshold of TBK1 Activation

Saul, Vera Vivian; Seibert, Markus; Krüger, Marcus; Jeratsch, Sylvia; Kracht, Michael; Schmitz, Michael Lienhard

regulators of cell metabolic pathways controlling glucose phosphorylation, pyruvate decarboxylation, fatty acid synthesis, and amino acid metabolism. This might indicate a role of SINT-speckles in metabolic regulation as a mediator of the cross talk between innate immunity and metabolism (Hotamisligil, 2017; Joseph et al., 2018; Jung et al., 2019) . Interestingly, the ULK kinases have also been implicated in the regulation of glucose metabolic fluxes and lipid metabolism (Ro et al., 2013) . In addition, metabolic processes co-determine effector functions and cell fate decisions of cells from the innate and adaptive immune systems (Ganeshan and Chawla, 2014; Odegaard and Chawla, 2013) . Vice versa, immunomodulatory signals such as cytokines directly regulate metabolic hormones or pathways (Kö nner and Brü ning, 2011; Matsuki et al., 2003) . The second largest group is formed by proteins involved in vesicle trafficking and autophagy, which is consistent with a previous study identifying ABIN2 as a hub protein binding to components of the endosomal sorting complex (Banks et al., 2016) . This set of interactors might be also relevant for the recently uncovered role of SINTBAD as a regulator of IL-15-induced autophagy , adding to the emerging role of innate immune signaling proteins such as TBK1 and TRAF6 for the formation of autophagosomes Pilli et al., 2012; Shi and Kehrl, 2010; Thurston et al., 2009) . The third largest group of the SINTBAD interactome comprises regulators of mitosis and components of the cytoskeleton, in line with previous reports, documenting a function of TBK1 as a centrosome-associated regulator of mitotic microtubule dynamics (Pillai et al., 2015; Kim et al., 2013) . Although this study focuses on the identification and cell biological characterization of SINT-speckles, future studies must comprehensively characterize the function(s) of constitutive and inducible SINT-speckles.