BORC, a Multisubunit Complex that Regulates Lysosome Positioning

Abstract

SUMMARY The positioning of lysosomes within the cytoplasm is emerging as a critical determinant of many lysosomal functions. Here we report the identification of a multi-subunit complex named BORC that regulates lysosome positioning. BORC comprises eight subunits, some of which are shared with the BLOC-1 complex involved in the biogenesis of lysosome-related organelles, and the others of which are products of previously uncharacterized open reading frames. BORC associates peripherally with the lysosomal membrane, where it functions to recruit the small GTPase Arl8. This initiates a chain of interactions that promotes the Kinesin-1-dependent movement of lysosomes toward the plus ends of microtubules in the peripheral cytoplasm. Interference with BORC or other components of this pathway results in collapse of the lysosomal population into the pericentriolar region. In turn, this causes reduced cell spreading and migration, highlighting the importance of BORC-dependent centrifugal transport for non-degradative functions of lysosomes.

Genome‐wide significant schizophrenia risk variation on chromosome 10q24 is associated with altered cis‐regulation of BORCS7, AS3MT, and NT5C2 in the human brain

“…BORCS7 encodes BLOC‐1‐related complex subunit 7 (Diaskedin), part of the recently described BLOC‐1‐related complex, which has been implicated in lysosomal function and cell migration [Pu et al, 2015]. AS3MT encodes arsenic methyltransferase, which has a known role in arsenic metabolism [Sumi and Himeno, 2012], although its functions in the brain are currently unclear.…”

Arf-like GTPase Arl8: Moving from the periphery to the center of lysosomal biology

“…36 Interestingly, the authors found that cells silenced for BORC subunit-myrlysin were defective in spreading and migration, implicating a conceivable involvement of these proteins during tumor metastasis. Further, the Arl8b-dependent pH control of lysosomal motility could be important for cellular behavior in acidic microenvironments, holding credible relevance to study of Arl8 function in cancer progression.…”

“…Although the identity of the Arl8 GEF and GAP remains unknown, recent studies have identified BORC (BLOC-one-related complex), a multi-subunit protein complex that regulate Arl8b recruitment to lysosomes, and thereby mediate kinesindependent lysosome transport toward the cell periphery. 36 BORC shares 3 of its 8 subunits with the BLOC-1 complex that is involved in the biogenesis of lysosome-related organelles. 37 The clustered regularly interspaced short palindromic repeats (CRISPR)-based knockout of the BORC-specific subunit, myrlysin, was shown to cause Arl8b detachment from lysosomes along with clustering of lysosomes in the perinuclear region (an effect also observed upon Arl8b depletion).…”

Mechanisms and functions of lysosome positioning

“…This kinesin is a heterotetramer composed of two heavy chains (KIF5A, KIF5B or KIF5C) and two light chains (KLC1, KLC2, KLC3 or KLC4) (DeBoer et al, 2008). Kinesin-1 is recruited to lysosomes by a chain of interacting proteins, including the multisubunit BLOC-1-related complex (BORC), the Arf-like small GTPase Arl8 (which has two isoforms in mammals, Arl8a and Arl8b, hereafter generically referred to as Arl8), and the Arl8 effector SifA and kinesin-interacting protein (SKIP, also known as PLEKHM2) (Boucrot et al, 2005;Bagshaw et al, 2006;Hofmann and Munro, 2006;Rosa-Ferreira and Munro, 2011;Pu et al, 2015) (Fig. 4).…”