Abnormal regulation of TSG101 in mice with spongiform neurodegeneration

Abstract

Summary Spongiform neurodegeneration is characterized by the appearance of vacuoles throughout the central nervous system. It has many potential causes, but the underlying cellular mechanisms are not well understood. Mice lacking the E3 ubiquitin ligase Mahogunin Ring Finger-1 (MGRN1) develop age-dependent spongiform encephalopathy. We identified an interaction between a “PSAP” motif in MGRN1 and the ubiquitin E2 variant (UEV) domain of TSG101, a component of the endosomal sorting complex required for transport I (ESCRT-I), and demonstrate that MGRN1 multimonoubiquitinates TSG101. We examined the in vivo consequences of loss of MGRN1 on TSG101 expression and function in the mouse brain. The pattern of TSG101 ubiquitination differed in the brains of wild-type mice and Mgrn1 null mutant mice: at 1 month of age, null mutant mice had less ubiquitinated TSG101, while in adults, mutant mice had more ubiquitinated, insoluble TSG101 than wild-type mice. There was an associated increase in epidermal growth factor receptor (EGFR) levels in mutant brains. These results suggest that loss of MGRN1 promotes ubiquitination of TSG101 by other E3s and may prevent its disassociation from endosomal membranes or cause it to form insoluble aggregates. Our data implicate loss of normal TSG101 function in endo-lysosomal trafficking in the pathogenesis of spongiform neurodegeneration in Mgrn1 null mutant mice.

The Roles of ESCRT Proteins in Healthy Cells and in Disease

“…Mutations in the ESCRT-III subunit CHMP2B, have been shown to cause FTD3 (Skibinski et al, 2005) and ALS (Parkinson et al, 2006). Furthermore, the ESCRTs' and their associated proteins are also indirectly implicated in causing spongiform neurodegeneration (Kim, et al, 2007;Jiao et al, 2009), spastic paraplegia (Reid et al, 2005) and Niemann-Pick type C neurodegeneration (Ohsaki et al, 2006). Sustained receptor signaling is a key event in carcinogenesis, and Tsg101 (Li et al, 1997, Sun et al, 1997Lin et www.intechopen.com…”

“…For instance, in mice, a null mutation in Mahoganin, an E3 ubiquitin ligase that ubiquitinates Tsg101, causes spongiform neurodegeneration, a recessively transmitted prion-like disease (Kim, et al, 2007;Jiao et al, 2009). Two putative ESCRT-III interacting proteins, spartin and spastin are mutated in spastic paraplegia, an inherited neurodegenerative disease that paralyzes the lower limbs (Reid et al, 2005).…”

Mahoganoid and Mahogany Mutations Rectify the Obesity of the Yellow Mouse by Effects on Endosomal Traffic of MC4R Protein

“…MGRN1 Interacts with and Ubiquitinates TSG101-TSG101 is an MGRN1 substrate (28,29). MGRN1 interacts with the ubiquitin E2 variant domain of TSG101 via a P(S/T)AP motif (a "late viral domain") found in the C-terminal half of all vertebrate MGRN1 orthologs; invertebrate MGRN1 proteins lack this motif.…”

“…Mechanism 3-Based on the functional interaction between MGRN1 and TSG101 (28,29), an essential component of the endosomal machinery required for receptor trafficking to the lysosome, we hypothesized that MGRN1 and likely ATRN are required for MC4R degradation. ASP binding to the melanocortin receptor in Xenopus melanophores (38) and to MC1R in B16 melanoma cells (42) blocks receptor signaling through both competitive antagonism and receptor down-regulation.…”

“…MGRN1 (mahogunin) multiubiquitinates tumor suppressor gene 101 (Tsg101), an essential component of the endosomal sorting complex required for transport-I (ESCRT-I) that is necessary for the proper trafficking of monoubiquitinated cell surface receptors from the plasma membrane to the lysosome for degradation (28,29). The precise cell physiological consequences of MGRN1-dependent ubiquitination of TSG101 are unknown.…”