Developmental Cell

Previews BORC and BLOC-1: Shared Subunits in Trafficking Complexes Lars Langemeyer1 and Christian Ungermann1,* 1Biochemistry Section, Department of Biology/Chemistry, University of Osnabru ¨ ck, Barbarastrasse 13, 49076 Osnabru¨ck, Germany *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2015.04.008

Intracellular trafficking requires careful positioning of organelles within the cellular three-dimensional space. Pu et al. (2015) now provide evidence for a multisubunit complex, named BORC, that regulates the positioning of lysosomes at the cell periphery and consequently affects cell migration. While much has been learned about the machinery of trafficking pathways over the last years, the function of organelle shape and intracellular positioning and the role of contacts between organelles are still incompletely understood. Many organelles are attached to the cytoskeleton and are repositioned in response to growth signals or during cell division. For instance, cells normally distribute their lysosomes to facilitate interaction with autophagosomes and endosomes in the context of organelle and protein turnover (Korolchuk et al., 2011). Lysosome positioning has also been linked to changes in intracellular pH and invasive movement of tumor cells (Steffan et al., 2010). A study in the current issue of Developmental Cell (Pu et al., 2015) now identifies a multisubunit complex with similarity to the BLOC-1 complex that regulates lysosome positioning by recruiting an adaptor of the microtubuleassociated kinesin motor to its surface. In metazoan cells, BLOC-1 is found on tubular endosomes and plays an important role in the biogenesis of lysosomerelated organelles (LRO) such as melanosomes, possibly by facilitating cargo sorting into tubular carriers (Di Pietro et al., 2006; Setty et al., 2007). While trying to identify novel interactors of BLOC-1, Pu et al. discovered a set of previously uncharacterized proteins (Pu et al., 2015). Due to their similar size and predicted coiled-coil domains, the authors suspected that these proteins might be previously unidentified subunits of the BLOC-1 complex. However, it turned out that the BLOC-1 subunits BLOS2 (used initially as bait), BLOS1, and Snapin are part of a separate complex, which the authors name the BORC complex (BLOC-one related com-

plex; Figure 1A). This complex consists of eight small proteins, and it localizes to the lysosome. Upon deletion of the BORC-specific subunit Myrlysin, the authors found that lysosomes cluster in the perinuclear region. The authors suspected that BORC might affect the attachment of lysosomes to the microtubule network, because a similar phenotype had been observed upon deletion of the small GTPase Arl8 (Rosa-Ferreira and Munro, 2011). In mammalian cells, lysosomes require Arl8 as an adaptor to recruit the cofactor SKIP and eventually the kinesin complex of KLC and KIF5 (Rosa-Ferreira and Munro, 2011). Strikingly, deletion of most of the BORC subunits resulted in relocalization of Arl8 to the cytosol, whereas other BORC-interacting proteins, such as the activator of the TOR1 kinase complex (mTORC1), the LamTOR complex, were unaffected. Also, BORC deletion mutants still functioned normally in endocytosis and mTORC1 activation (Pu et al., 2015). However, cells lacking the BORC subunit Myrlysin appeared smaller, which seemed to be a consequence of impaired cell spreading rather than the overall size. In agreement with this, the authors found a strong deficiency in cell migration in Myrlysin knockout cells, providing a link between organelle positioning and cellular function (Figure 1). BORC is critical for Arl8 recruitment, though the obvious function as an Arl8 guanine exchange factor (GEF) could not be confirmed. Rather, it appears that BORC may pave the way for an Arl8 GEF, possibly as a cofactor of the recruitment system. Such a function would be comparable to yeast BLOC-1, which binds the Rab GTPase activating protein (GAP) Msb3 and thus controls yeast

Rab5 levels on endosomes (John Peter et al., 2013) (Figures 1B and 1C). Another possibility is that BORC is involved in shaping lysosomes, which may be required for Arl8 recruitment. BLOC-1 has been localized to tubular endosomes (Di Pietro et al., 2006), suggesting the possibility of a common function of both complexes in shaping organelles or recognizing the shape of a membrane. However, the initial recruitment factor on endosomes or lysosomes has not been identified for either BORC or BLOC-1. It is noteworthy that yeast BLOC-1 is an effector of yeast Rab5 and becomes soluble in its absence (John Peter et al., 2013), and a similar interaction might also occur in metazoan cells. The identification of BORC also sheds light on the ambiguous observations in studies that focused on different BLOC-1 deletions, some of which reported embryonic lethality in mice (Zhang et al., 2014), whereas others just coat color changes (Dell’Angelica, 2004). Because three subunits are shared between BORC and BLOC-1, loss of any shared components will likely result in mislocalization and possibly, as observed for yeast BLOC-1 (John Peter et al., 2013), disassembly of both complexes and hence a stronger phenotype. The characterization of BORC provides another example of shared subunits in a complex involved in trafficking, transport, and signaling, similar to the presence of Vps11, 16, 18, and 33 in both the HOPS and CORVET tethering complexes (Balderhaar and Ungermann, 2013). This arrangement could be used for co-regulation of complexes via the shared subunits, or to enable crosstalk between pathways. Alternatively, all these complexes may just take advantage of common features

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Dell’Angelica, E.C. (2004). Curr. Opin. Cell Biol. 16, 458–464. Di Pietro, S.M., Falco´n-Pe´rez, J.M., Tenza, D., Setty, S.R.G., Marks, M.S., Raposo, G., and Dell’Angelica, E.C. (2006). Mol. Biol. Cell 17, 4027–4038. John Peter, A.T., Lachmann, J., Rana, M., Bunge, M., Cabrera, M., and Ungermann, C. (2013). J. Cell Biol. 201, 97–111. Korolchuk, V.I., Saiki, S., Lichtenberg, M., Siddiqi, F.H., Roberts, E.A., Imarisio, S., Jahreiss, L., Sarkar, S., Futter, M., Menzies, F.M., et al. (2011). Nat. Cell Biol. 13, 453–460.

Figure 1. Functions of BORC and BLOC-1 (A) Composition of BORC and BLOC-1. (B) BORC is a resident lysosomal complex that promotes Arl8 recruitment and thereby microtubule-dependent lysosomal positioning. (C) BLOC-1 is found on tubular endosomes and is required for the biogenesis of lysosome-related organelles (LROs). The connection to Rab5 and the yeast Rab5 GAP, Msb3, are suggested based on findings in yeast. See text for details.

of the shared subunits, without any coregulation or crosstalk between them. Structural and functional analyses in their cellular contexts will be important to understand common functions of shared subunits within these complexes. Certainly, further studies on BORC, BLOC-1, and beyond will shed light on possible connections and co-regulation.

ACKNOWLEDGMENTS Work in the authors’ laboratory is supported by the DFG (SFB 944, project P11) and by the Hans-Mu¨hlenhoff foundation (to C.U.).

Pu, J., Schindler, C., Jia, R., Jarnik, M., Backlund, P., and Bonifacino, J.S. (2015). Dev. Cell 33, this issue, 176–188. Rosa-Ferreira, C., and Munro, S. (2011). Dev. Cell 21, 1171–1178. Setty, S.R.G., Tenza, D., Truschel, S.T., Chou, E., Sviderskaya, E.V., Theos, A.C., Lamoreux, M.L., Di Pietro, S.M., Starcevic, M., Bennett, D.C., et al. (2007). Mol. Biol. Cell 18, 768–780. Steffan, J.J., Williams, B.C., Welbourne, T., and Cardelli, J.A. (2010). J. Cell Sci. 123, 1151– 1159.

REFERENCES Balderhaar, H.J.K., and Ungermann, C. (2013). J. Cell Sci. 126, 1307–1316.

Zhang, A., He, X., Zhang, L., Yang, L., Woodman, P., and Li, W. (2014). J. Biol. Chem. 289, 29180– 29194.

Crumbling under Pressure Frank M. Mason1 and Adam C. Martin1,* 1Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.devcel.2015.04.005

In order for an organism to maintain its form, it must be able to withstand physical perturbation, including the pull of gravity. A recent study in Nature from Porazinski and colleagues (2015) suggests that mechanisms promoting tissue tension are critical to resist the Earth’s downward pull. During the development of an organ or embryo, physical forces influence the final shape and form of tissues. Additionally, embryos must be able to withstand environmental perturbations, such as gravity. D’Arcy Thompson postulated that ‘‘the forms as well as the actions of our bodies are entirely conditioned by the strength of gravity upon this globe’’ (Thompson, 1917). A new study in Nature demonstrates that,

without the proper function of one gene, gravity can flatten an embryo (Porazinski et al., 2015). A screen for genes required for medaka fish development identified a mutant (hirami), which mapped to the YAP transcription factor locus (Porazinski et al., 2015). These YAP mutants had improperly shaped or flattened embryos, and, interestingly, embryo collapse correlated with orientation relative to the

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gravitational pull of earth. The authors hypothesized that embryo collapse could be due to reduced tension needed to counter gravity. Laser cutting and micropipette aspiration experiments demonstrated that YAP mutants had lowered embryonic tissue tension. Actomyosin activity has been shown to promote tissue stiffness in embryos and thus resistance to applied force (Zhou et al., 2009).

BORC and BLOC-1: Shared subunits in trafficking complexes.

Intracellular trafficking requires careful positioning of organelles within the cellular three-dimensional space. Pu et al. (2015) now provide evidenc...
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