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

SINT-speckles might also be of pathophysiological relevance in virus infections or protein aggregation diseases. This study shows that a significant fraction of the phlebovirus NSs protein colocalize with ABIN2. It will be interesting to investigate the functional consequences of this association as well as the molecular mechanisms leading to this interaction, as the NSs protein is a structured protein (Barski et al., 2017) . ABIN2 is also bound by the rabies virus-encoded M protein, which in turn controls the expression of inflammatory target genes (Besson et al., 2017) , and also other components of SINT-speckles assigned to the functional group ''inflammation and infection'' (see Figure 5D ) is targeted by viruses or involved in the antiviral response (Schmitz et al., 2014) . Another possible pathophysiological scenario is due to the function of MLOs as signaling hubs in a crowded microenvironment, which can come at the cost of unwanted protein aggregation. Interestingly, partial loss of TBK1 causes protein misfolding diseases, namely, familial amyotrophic lateral sclerosis and frontotemporal dementia (Freischmidt et al., 2015; Gijselinck et al., 2015) . Also, mutations in TBK1 and its substrate protein optineurin contribute to frontotemporal lobar degeneration (Le Ber et al., 2015; Pottier et al., 2015) . This disease is also associated with an elevated SINTBAD expression (Broce et al., 2018) , and it will be very interesting to reveal in future studies whether the formation and function of SINT-speckles is affected in neurodegenerative diseases.