Recombinant Human Transforming growth factor beta activator LRRC33 (NRROS), partial

Function

Key regulator of transforming growth factor beta-1 (TGFB1) specifically required for microglia function in the nervous system (By similarity). Required for activation of latent TGF-beta-1 in macrophages and microglia: associates specifically via disulfide bonds with the Latency-associated peptide (LAP), which is the regulatory chain of TGFB1, and regulates integrin-dependent activation of TGF-beta-1 (By similarity). TGF-beta-1 activation mediated by LRRC33/NRROS is highly localized: there is little spreading of TGF-beta-1 activated from one microglial cell to neighboring microglia, suggesting the existence of localized and selective activation of TGF-beta-1 by LRRC33/NRROS (By similarity). Indirectly plays a role in Toll-like receptor (TLR) signaling: ability to inhibit TLR-mediated NF-kappa-B activation and cytokine production is probably a consequence of its role in TGF-beta-1 signaling (PubMed:23545260)

Subcellular Location

Cell membrane (Single-pass type I membrane protein); Endoplasmic reticulum membrane (Single-pass type I membrane protein)

Disease Association

Seizures, early-onset, with neurodegeneration and brain calcification (SENEBAC) : An autosomal recessive neurodegenerative disorder clinically characterized by refractory seizures apparent in the first year of life, mild early developmental delay, and developmental regression after seizure onset. Other features include hypotonia, hyperreflexia, peripheral spasticity, poor eye contact, absent speech, poor head control, and inability to walk. Brain imaging shows reduced white matter volume with delayed myelination, and punctate calcifications. [The protein represented in this entry is involved in disease pathogenesis]

Tissue Specificity

Mainly expressed in cells of hematopoietic origin (PubMed:29909984). Highly expressed in bone marrow, thymus, liver, lung, intestine and spleen (PubMed:23545260). In the brain, highly expressed in microglia (PubMed:32100099)

Subunit

Interacts with TGFB1; associates via disulfide bonds with the Latency-associated peptide chain (LAP) regulatory chain of TGFB1, leading to regulate activation of TGF-beta-1 (PubMed:29909984). Interacts (via LRR repeats) with TLR2, TLR3, TLR4, TLR9 and probably other Toll-like receptors (PubMed:23545260). Interacts with CYBB/NOX2; the interaction is direct (By similarity)

• Clark H.F. et al. The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. — Genome Res. (2003)
• Muzny D.M. et al. The DNA sequence, annotation and analysis of human chromosome 3. — Nature (2006)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Liu J. et al. Identification and characterization of a unique leucine-rich repeat protein (LRRC33) that inhibits Toll-like receptor-mediated NF-kappa-B activation. — Biochem. Biophys. Res. Commun. (2013)
• Qin Y. et al. A milieu molecule for TGF-beta required for microglia function in the nervous system. — Cell (2018)
• Smith C. et al. Biallelic mutations in NRROS cause an early onset lethal microgliopathy. — Acta Neuropathol. (2020)
• Dong X. et al. Bi-allelic LoF NRROS Variants Impairing Active TGF-beta1 Delivery Cause a Severe Infantile-Onset Neurodegenerative Condition with Intracranial Calcification. — Am. J. Hum. Genet. (2020)