Multisystem Proteinopathy (MSP) is a disease that causes some combination of inclusion body myopathy with rimmed vacuoles, Paget’s disease of bone, and ALS/FTD. Several different genes give rise to the unique phenotypic expression of MSP. Given the variety of genes that cause MSP and the specificity of the phenotype and tissue involvement, we asked; what are the unifying pathogenic features of MSP? To address this, we examined three areas of interest: stress granules, autophagy, and myogenesis. The currently identified roster of MSP genes have several structural and functional commonalities which fall into two categories: LC3B-intracting domain containing autophagy adaptors (SQSTM1, VCP, OPTN) and prion-like domain containing stress granule proteins (HNRNPA2B1, HNRNPA1, MATR3, TIA1). Previous studies identified that a non-pathogenic variant of the non-classical MSP protein, TIA1 N357S , can act as a phenotype modifier with SQSTM1P392L leading to distal muscle weakness rather than proximal muscle weakness seen with monogenic SQSTM1 mutations. Here we show that the same TIA1 variant is able to act as a modifier with VCP R159H to produce the same distal weakness. We established three major findings: 1) The non-classical MSP gene TIA1 N357S can modify the myopathy phenotype of both VCP and SQSTM1 to produce distal rather than proximal muscle weakness at the onset of disease, and that TIA1b expression drives the increase of TIA1 expression in diseased muscle and also fails to colocalize with SQSTM1—implying that upregulation of TIA1b is important for muscle stress response and also that TIA1b stress granules have reduced clearance by autophagy. 2) VCP and SQSTM1 both exhibit lysosome accumulation, which may be an emergent feature of inclusion body myopathies. 3) Impaired myogenesis via resistance to the master regulator of myogenesis MyoD, is a feature of MSP.