JASN312Editorial 233..240

glomeruli, this spatial segregation is even more pronounced. Using super-resolution microscopy, Subramanian et al. show the INF2 N-fragment accumulates in foot processes, whereas the C-fragment remains in the cell body. Although FSGS-associated mutations did not affect proteolytic cleavage of INF2, an INF2 N-fragment bearing the FSGS-associated R218Q mutation had greatly reduced ability to accumulate at cell edges or in foot processes. Importantly, the authors also show the INF2(R218Q) N-fragment can dimerize with the wild-type N-fragment and prevent the wild type from being recruited to cell edges, providing a potential explanation for the dominant mode of inheritance of INF2-associated FSGS. Finally, pointing to possible significance for INF2 in other kidney diseases, the authors noted that INF2 N-fragment localization correlated with podocyte health in Alport syndrome and in lupus nephritis. That is, among glomeruli from patients with these conditions, the INF2 N-fragment was present in normal-appearing foot processes, but absent from regions exhibiting foot process effacement (FPE), while in all cases the C-fragment remained in the podocyte cell body. Based on these combined results, Subramanian and colleagues propose a model whereby, after cathepsin cleavage, the DIDcontaining INF2 N-fragment enters the foot processes to inhibit resident mDIA formins. Since the FH2-containing C-fragment is retained in the cell body through anchorage to the endoplasmic reticulum, the net effect is an inhibition of formin-mediated actin assembly in the foot processes. The correlation between INF2 N-fragment mislocalization and occurrence of FPE hints that disinhibitionofmDIA formins in absence of INF2-DIDmight play a role in FPE. Studies from zebrafish provide support for this, where knockdown of INF2 expression results in FSGS-like phenotypes that are reversed by knockdown of fish DIA2 formin.8 mDIA formins are frequently associated with the assembly of contractile actin filament structures, and cultured podocytes exhibit apparent increased mDIA-dependent contractility with loss of INF2 N-fragment function. Intriguingly, contractile actin structures are normally absent from podocyte foot processes, but have been noted to accumulate at the basal aspect of podocytes in a number of kidneydiseases, including FSGS.9Although it is unclear whether appearance of those contractile structures is cause or effect of FPE, the results presented here hint that, in INF2-dependent FSGS, increased contractility may be causative. Important remaining questions are the identity of binding partners for the INF2 N-fragment in glomeruli, and understanding of why the INF2 N-fragment becomes displaced from foot processes in other kidneydiseases. Thesefindings also have implications for other cell types, as cathepsin-mediated cleavage of INF2 also occurred in nonpodocyte HEK293T cells. Thus, these exciting results indicate that actin cytoskeletal regulation via this novel crosstalk between different formins may be a common mode of formin activity.