ARF-Like (ARL) Proteins - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 223

ablated their ARL2 GAP activity (Ivanova et al. 2014 ). SigmaR1 is an incompletely
understood receptor but implicated in an impressive array of human diseases and
brain functions (Bourrie et al. 2004 ; Marrazzo et al. 2005 ; Hashimoto 2009 , 2013 ;
van Waarde et al. 2011 ; Kourrich et al. 2012 ; Niitsu et al. 2012 ; Bhuiyan
et al. 2013 ). A number of agonists and antagonists are known for SigmaR1 and
many are in clinical use today, making its binding to ELMODs of particular
interest. Currently the best characterized molecular function of Sigma1R is as a
chaperone for regulators of calcium signaling and cell survival pathways (Hayashi
and Su 2007 ; Mori et al. 2013 ). Thus, ELMODs, or the ARF family members they
act upon, may play important regulatory roles in one or more of these functions
linked to SigmaR1.
ELMOD2 has the highest levels of GAP activities against ARF family members
in vitro and has been linked in different ways to human biology or disease. Genetic
mapping of six families with familial idiopathic fibrosis (IPF) identified a single
haplotype associated with the disease containing ELMOD2 and another
uncharacterized gene (Hodgson et al. 2006 ). Of the two genes only ELMOD2
mRNA expression levels were reduced in the lungs of IPF patients compared to a
control group, identifying ELMOD2 as a candidate gene for IPF. Overexpression
and knockdown studies of ELMOD2 in A549 cells revealed a potential link
between ELMOD2 and antiviral gene expression (Pulkkinen et al. 2010 ).
ELMOD2 localizes to lipid droplets, based upon its presence in several proteomics
studies of lipid droplets (Hodges and Wu 2010 ; Bouchoux et al. 2011 ) and the
finding that epitope-tagged ELMOD2-HA was present on lipid droplets in HeLa
cells stimulated with oleic acid (East et al. 2012 ). There is currently no information
regarding the function of ELMOD2 at lipid droplets.
Studies in HeLa cells also revealed a role for ELMOD2 as an ARL2 effector in
mitochondria. ELMOD2 localized to the mitochondrial matrix and knockdown of
ELMOD2 resulted in mitochondrial fragmentation and clustering around the
nucleus, phenocopying depletion of ARL2 (L. Newman, C. Zhang, and
R.A. Kahn, unpublished observations). It may appear counterintuitive that a GAP,
often viewed as acting antagonistically to its target GTPase, is found to mimic or
phenocopy its substrate. However, we have argued previously (East and Kahn
2011 ) that many, perhaps all, ARF family GAPs function as both temporal regula-
tors of GTPase signaling and effectors of their substrate GTPases. As effectors they
become key downstream components in propagation of the relevant biological
signal.
ELMOD1 and ELMOD3 have been linked to deafness in mice and humans,
respectively, with proposed roles in the proper function and/or maintenance of
stereocilia. Two randomly occurring, allelic mutations resulting in deafness in mice
have both been linked to ELMOD1 (Johnson et al. 2012 ). Scanning electron
microscopy of cochlear hair cells revealed progressively worsening stereocilia
abnormalities including degeneration, fusion, elongation, and complete loss.
Stereocilia are actin-based cilia essential to the mechanoelectrical transduction
process in hearing. In newborn mice, stereocilia were normal, indicating that
stereocilia development was not affected. Thus, ELMOD1 appears to have some